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{{Short description|Class of immunomodulatory drugs}}
{{Redirect|IMiD|IMID|immune-mediated inflammatory diseases}}
{{Infobox drug class
| Image
| Alt
| Caption = Thalidomide
| Use = [[Erythema nodosum leprosum]], [[multiple myeloma]], [[myelodysplastic syndrome]], [[acute myeloid leukaemia]] and other immunologic conditions
| ATC_prefix
| Drugs.com
| Biological_target = [[Tumour necrosis factor|TNF]], [[interleukin 6|IL-6]], [[Vascular endothelial growth factor|VEGF]], [[NF-kB]], etc.
}}
'''Cereblon E3 ligase modulators''', also known as '''immunomodulatory imide drugs''' ('''IMiDs'''), are a class of [[immunotherapy#Immunomodulators|immunomodulatory drugs]]<ref name = pmid_16085014>{{cite journal|last=Knight|first=R|title=IMiDs: a novel class of immunomodulators.|journal=Seminars in Oncology|date=August 2005|volume=32|issue=4 Suppl 5|pages=S24–S30|doi=10.1053/j.seminoncol.2005.06.018|pmid=16085014}}</ref> (drugs that adjust [[immune system|immune responses]]) containing an [[imide]] group. The IMiD class includes [[thalidomide]] and its analogues ([[lenalidomide]], [[pomalidomide]], [[mezigdomide]]
and [[iberdomide]]).<ref name = pmid_16085014/> These drugs may also be referred to as 'Cereblon modulators'. [[Cereblon]] (CRBN) is the protein targeted by this class of drugs.
The name "IMiD" [[allusion|alludes]] to both "IMD" for "immunomodulatory drug" and the forms ''[[imide]]'', ''[[wikt:imido-|imido-]]'', ''[[wikt:imid-|imid-]]'', and ''[[wikt:imid|imid]]''.
The development of analogs of thalidomide was precipitated by the discovery of the [[Angiogenesis inhibitor|anti-angiogenic]] and [[anti-inflammatory]] properties of the drug yielding a new way of fighting cancer as well as some inflammatory diseases after it had been banned in 1961. The problems with thalidomide included teratogenic side effects, high incidence of other adverse reactions, poor solubility in water and poor absorption from the intestines.
In 1998 thalidomide was approved by the U.S. [[Food and Drug Administration]] (FDA) for use in newly diagnosed [[multiple myeloma]] (MM) under strict regulations.<ref>{{cite journal |vauthors=Aragon-Ching AB, Li H, Gardner ER, Figg WD |title=Thalidomide analogues as anticancer drugs |journal=Recent Pat Anti-Cancer Drug Discov |volume=2 |issue=2 |pages=167–174 |year=2007 |pmc=2048745 |doi=10.2174/157489207780832478 |pmid=17975653}}</ref> This has led to the development of a number of [[structural analog|analogs]] with fewer [[side effects]] and increased [[Potency (pharmacology)|potency]] which include [[lenalidomide]] and [[pomalidomide]], which are currently marketed and manufactured by [[Celgene]].
==History==
{{main|Thalidomide}}
Thalidomide was originally released in the ''Federal Republic of Germany'' (West Germany) under the label of ''Contergan'' on October 1, 1957, by ''Chemie Grünenthal'' (now [[Grünenthal]]). The drug was primarily prescribed as a [[sedative]] or hypnotic, but it was also used as an [[antiemetic]] for morning sickness in pregnant women. The drug was banned in 1961 after its [[teratology|teratogenic]] properties were observed. The problems with thalidomide were, aside from the teratogenic side effects, both high incidence of other [[adverse reaction]]s along with poor [[solubility]] in water and [[absorption (pharmacokinetics)|absorption]] from the [[intestines]].<ref name="oncozine.com">[http://oncozine.com/profiles/blogs/how-a-vilified-drug-became-a-life-saving-agent-against-cancer Reversal of Fortune: How a Vilified Drug Became a Life-saving Agent in the "War" Against Cancer - Onco'Zine - The International Oncology Network (November 30, 2013)] {{webarchive|url=https://archive.today/20140103191615/http://oncozine.com/profiles/blogs/how-a-vilified-drug-became-a-life-saving-agent-against-cancer |date=January 3, 2014 }}</ref><ref name=Mazzoccoli2012>{{cite journal|last=Mazzoccoli|first=L|author2=Cadoso, SH |author3=Amarante, GW |author4=de Souza, MV |author5=Domingues, R |author6=Machado, MA |author7=de Almeida, MV |author8=Teixeira, HC |title=Novel thalidomide analogues from diamines inhibit pro-inflammatory cytokine production and CD80 expression while enhancing IL-10.|journal=Biomedicine & Pharmacotherapy|date=July 2012|volume=66|issue=5|pages=323–9|pmid=22770990|doi=10.1016/j.biopha.2012.05.001}}</ref> Adverse reactions include [[peripheral neuropathy]] in large majority of patients, [[constipation]], [[thromboembolism]] along with [[dermatology|dermatological]] complications.<ref name = Prommer2009>{{cite journal|last=Prommer|first=E. E.|title=Review Article: Palliative Oncology: Thalidomide|journal=American Journal of Hospice and Palliative Medicine|date=20 October 2009|volume=27|issue=3|pages=198–204|doi=10.1177/1049909109348981|pmid=19843880|s2cid=24167431}}</ref>
Four years after thalidomide was withdrawn from the market for its ability to induce severe birth defects, its anti-inflammatory properties were discovered when patients with [[Erythema nodosum|erythema nodosum leprosum (ENL)]] used thalidomide as a sedative and it reduced both the clinical signs and symptoms of the disease. Thalidomide was discovered to inhibit [[tumour necrosis factor-alpha]] (TNF-α) in 1991 (5a Sampaio, Sarno, Galilly Cohn and Kaplan, JEM 173 (3) 699–703, 1991) . TNF-α is a [[cytokine]] produced by [[macrophages]] of the immune system, and also a mediator of inflammatory response. Thus the drug is effective against some inflammatory diseases such as ENL (6a Sampaio, Kaplan, Miranda, Nery..... JID 168 (2) 408-414 2008). In 1994 Thalidomide was found to have anti-angiogenic activity<ref name="ncbi.nlm.nih.gov">{{cite journal|title= Thalidomide is an inhibitor of angiogenesis|pmid=7513432 | volume=91|issue=9 |pmc=43727|date=April 1994|vauthors=D'Amato RJ, Loughnan MS, Flynn E, Folkman J |journal=Proc. Natl. Acad. Sci. U.S.A.|pages=4082–5|doi= 10.1073/pnas.91.9.4082 |bibcode=1994PNAS...91.4082D |doi-access=free }}</ref> and anti-tumor activity<ref name="nih">{{cite journal|title= Combination oral antiangiogenic therapy with thalidomide and sulindac inhibits tumour growth in rabbits|pmid=10408702 | doi=10.1038/sj.bjc.6690020|volume=79|issue=1 |pmc=2362163|date=January 1999|vauthors=Verheul HM, Panigrahy D, Yuan J, D'Amato RJ |journal=Br. J. Cancer|pages=114–8}}</ref> which propelled the initiation of clinical trials for cancer including multiple myeloma. The discovery of the anti-inflammatory, anti-angiogenic and anti-tumor activities of thalidomide increased the interest of further research and [[chemical synthesis|synthesis]] of safer analogs.<ref name=Bartlett2004>{{cite journal|last=Bartlett|first=J. Blake|author2=Dredge, Keith |author3=Dalgleish, Angus G. |title=Timeline: The evolution of thalidomide and its IMiD derivatives as anticancer agents|journal=Nature Reviews Cancer|date=1 April 2004|volume=4|issue=4|pages=314–322|doi=10.1038/nrc1323|pmid=15057291|s2cid=7293027}}</ref><ref name="ReferenceA">{{cite journal|title= Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma|pmid=11740816 | doi=10.1016/S0093-7754(01)90031-4|volume=28|issue=6 |date=December 2001|vauthors=D'Amato RJ, Lentzsch S, Anderson KC, Rogers MS |journal=Semin. Oncol.|pages=597–601}}</ref>
Lenalidomide is the first analog of thalidomide which is marketed. It is considerably more potent than its parent drug with only two differences at a molecular level, with an added [[amino group]] at position 4 of the phthaloyl ring and removal of a [[carbonyl]] group from the phthaloyl ring.<ref name=Zimmerman2009>{{cite journal|last=Zimmerman|first=Todd|title=Immunomodulatory agents in oncology|journal=Update on Cancer Therapeutics|date=1 May 2009|volume=3|issue=4|pages=170–181|doi=10.1016/j.uct.2009.03.003}}</ref>
Development of lenalidomide began in the late 1990s and clinical trials of lenalidomide began in 2000. In October 2001 lenalidomide was granted orphan status for the treatment of MM. In mid-2002 it entered phase II and by early 2003 phase III. In February 2003 FDA granted fast-track status to lenalidomide for the treatment of relapsed or refractory MM.<ref name=Bartlett2004 />
In 2006 it was approved for the treatment of MM along with dexamethasone and in 2007 by [[European Medicines Agency]] (EMA). In 2008, phase II trial observed efficacy in treating [[Non-Hodgkin lymphoma|Non-Hodgkin's lymphoma]].<ref name=Zeldis2011>{{cite journal|last=Zeldis|first=Jerome B.|author2=Knight, Robert |author3=Hussein, Mohamad |author4=Chopra, Rajesh |author5= Muller, George |title=A review of the history, properties, and use of the immunomodulatory compound lenalidomide|journal=Annals of the New York Academy of Sciences|date=1 March 2011|volume=1222|issue=1|pages=76–82|doi=10.1111/j.1749-6632.2011.05974.x |pmid=21434945|bibcode=2011NYASA1222...76Z|s2cid=5336195}}</ref>
Pomalidomide (3-aminothalidomide) was the second thalidomide analog to enter the clinic being more potent than both of its predecessors.<ref>{{Cite web|url=http://vectorblog.org/2013/04/from-thalidomide-to-pomalyst-better-living-through-chemistry/|title = Vector has moved}}</ref>
First reported in 2001, pomalidomide was noted to directly inhibit myeloma cell proliferation and thus inhibiting MM both on the tumor and vascular compartments.<ref name="D'Amato2001">{{cite journal|last=D'Amato|first=RJ|author2=Lentzsch, S |author3=Anderson, KC |author4= Rogers, MS |title=Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma.|journal=Seminars in Oncology|date=December 2001|volume=28|issue=6|pages=597–601|pmid=11740816|doi=10.1016/S0093-7754(01)90031-4}}</ref> This dual activity of pomalidomide makes it more efficacious than thalidomide both ''in vitro'' and ''in vivo''.<ref name="nih2">{{cite journal|title= S-3-Amino-phthalimido-glutarimide inhibits angiogenesis and growth of B-cell neoplasias in mice|pmid=11956087 | volume=62|issue=8 |date=April 2002|vauthors=Lentzsch S, Rogers MS, LeBlanc R |journal=Cancer Res.|pages=2300–5|display-authors=etal}}</ref> This effect is not related to TNF-α inhibition since potent TNF-α inhibitors such as rolipram and pentoxifylline did not inhibit myeloma cell growth nor angiogenesis.<ref name="ReferenceA"/> Upregulation of interferon gamma, IL-2 and IL-10 have been reported for pomalidomide and may contribute to its anti-angiogenic and anti-myeloma activities.
[[File:Chronology-TLP.png|center|1000px|thumb|'''Figure 1:''' Chronological view of the history of thalidomide and its analogs]]
==Development==
The thalidomide molecule is a synthetic derivative of [[glutamic acid]] and consists of a glutarimide ring and a phthaloyl ring (Figure 5).<ref name=Man2009>{{cite journal|last=Man|first=Hon-Wah|author2=Schafer, Peter |author3=Wong, Lu Min |author4=Patterson, Rebecca T. |author5=Corral, Laura G. |author6=Raymon, Heather |author7=Blease, Kate |author8=Leisten, Jim |author9=Shirley, Michael A. |author10=Tang, Yang |author11=Babusis, Darius M. |author12=Chen, Roger |author13=Stirling, Dave |author14=Muller, George W. |title=Discovery of (''S'')-''N''-<nowiki/>{2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1''H''-isoindol-4-yl}acetamide (Apremilast), a Potent and Orally Active Phosphodiesterase 4 and Tumor Necrosis Factor-α Inhibitor|journal=Journal of Medicinal Chemistry|date=26 March 2009|volume=52|issue=6|pages=1522–4|doi=10.1021/jm900210d|pmid=19256507}}</ref><ref name=Muller1996>{{cite journal|last=Muller|first=George W.|author2=Corral, Laura G. |author3=Shire, Mary G. |author4=Wang, Hua |author5=Moreira, Andre |author6=Kaplan, Gilla |author7= Stirling, David I. |title=Structural Modifications of Thalidomide Produce Analogs with Enhanced Tumor Necrosis Factor Inhibitory Activity|journal=Journal of Medicinal Chemistry|date=1 January 1996|volume=39|issue=17|pages=3238–3240|doi=10.1021/jm9603328|pmid=8765505}}</ref> Its [[International Union of Pure and Applied Chemistry|IUPAC]] name is 2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione and it has one chiral center<ref name=Man2009 />
After thalidomide's selective inhibition of TNF-α had been reported, a renewed effort was put in thalidomide's clinical development. The clinical development led to the discovery of new analogs which strived to have improved activities and decreased side effects.<ref name=Bartlett2004 /><ref name=Man2003>{{cite journal|last=Man|first=Hon-Wah|author2=Corral, Laura G |author3=Stirling, David I |author4= Muller, George W |title=α-Fluoro-substituted thalidomide analogues|journal=Bioorganic & Medicinal Chemistry Letters|date=1 October 2003|volume=13|issue=20|pages=3415–3417|doi=10.1016/S0960-894X(03)00778-9|pmid=14505639}}</ref>
Clinically, thalidomide has always been used as a [[Racemic mixture|racemate]]. Generally the ''S''-[[isomer]] is associated with the infamous teratogenic effects of thalidomide and the ''R''-isomer is devoid of the teratogenic properties but conveys the sedative effects,<ref name=Bartlett2004 /> however this view is highly debated and it has been argued that the animal model that these different ''R''- and ''S''-effects were seen in was not sensitive to the thalidomide teratogenic effects. Later reports in rabbits, which is a sensitive species, unveiled teratogenic effects from both isomers.<ref name=Bartlett2004 /><ref name=Man2009 /><ref name=Muller1996 /><ref name=Man2003 /> Moreover, thalidomide enantiomers have been shown to be [[Racemization|interconversed]] ''in vivo'' due to the acidic chiral hydrogen in the asymmetric center (shown, for the EM-12 analog, in Figure 3),<ref name=Muller1996 /><ref name=Man2003 /> so the plan to administer a purified single [[enantiomer]] to avoid the teratogenic effects will most likely be in vain.<ref name=Bartlett2004 /><ref name=Man2009 /><ref name=Muller1996 />
===Development of lenalidomide and pomalidomide===
[[File:EM-12 with chiral hydrogen highlighted.svg|thumb|right|250px|'''Figure 3:''' Molecular structure of EM-12, an analog of thalidomide. The acidic chiral hydrogen is highlighted]]
One of the analogs of interest was made by isoindolinone replacement of the phthaloyl ring. It was given the name EM-12 (Figure 3). This replacement was thought to increase the [[bioavailability]] of the substance because of increased stability. The molecule had been reported to be an even more potent teratogenic agent than thalidomide in rats, rabbits and monkeys. Additionally, these analogs are more potent inhibitors of angiogenesis than thalidomide.<ref name="D'Amato2001"/> As well, the amino-thalidomide and amino-EM-12 were potent inhibitors of TNF-α.<ref name=Muller1996 /> These two analogs later got the name lenalidomide, which is the EM-12 amino analog, and pomalidomide, the thalidomide amino analog.<ref name=Bartlett2004 />
{{Clear}}
==Medical use==
Line 21 ⟶ 50:
* [[Myelodysplastic syndrome]], a precursor condition to [[acute myeloid leukaemia]]
* [[Erythema nodosum
* [[Multiple myeloma]]
Off-label indications for which they seem promising treatments include:<ref name = Haem2012>{{cite journal|last=Vallet|first=S|author2=Witzens-Harig, M |author3=Jaeger, D |author4= Podar, K |title=Update on immunomodulatory drugs (IMiDs) in hematologic and solid malignancies|journal=Expert Opinion on Pharmacotherapy|date=March 2012|volume=13|issue=4|pages=473–494|doi=10.1517/14656566.2012.656091|pmid=22324734|s2cid=7981368}}</ref>
* [[
* [[AL amyloidosis|Light chain-associated (AL)
*
* [[Acute myeloid leukaemia]] (AML)
* [[Prostate cancer]]
* Metastatic [[renal cell carcinoma]] (mRCC)
===Thalidomide===
Thalidomide has been approved by the FDA for ENL and MM in combination with [[dexamethasone]]. EMA has also approved it to treat MM in combination with [[prednisone]] and/or [[melphalan]]. Orphan indications by the FDA include [[graft-versus-host disease]], mycobacterial infection, recurrent [[aphthous ulcers]], severe recurrent [[aphthous stomatitis]], primary brain malignancies, AIDS-associated [[wasting]] syndrome, [[Crohns|Crohn's]] disease, [[Kaposi's sarcoma]], [[myelodysplastic syndrome]] and [[hematopoietic stem cell transplantation]].<ref name=ThalidomidSmPC2>{{cite web|title=Thalomid (Thalidomide) dosing, indications, interactions, adverse effects, and more.|url=http://reference.medscape.com/drug/thalomid-thalidomide-343211|publisher=MedScape reference|access-date=18 September 2012}}</ref><ref>{{cite web|title=Thalidomide Celgene (previously Thalidomide Pharmion)|url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000823/human_med_001090.jsp&mid=WC0b01ac058001d124|publisher=European Medicines Agency|access-date=18 September 2012}}</ref>
===Lenalidomide===
Lenalidomide is approved in nearly 70 countries, in combination with dexamethasone for the treatment of patients with MM who have received at least one prior therapy. Orphan indications include [[diffuse large B-cell lymphoma]], [[B-cell chronic lymphocytic leukemia|chronic lymphocytic leukemia]] and [[mantle cell lymphoma]].
Lenalidomide is also approved for transfusion-dependent [[anemia]] due to low or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities in the U.S., Canada, Switzerland, Australia, New Zealand, Malaysia, Israel and several Latin American countries, while [[Marketing Authorization Application|marketing authorization application]] is currently being evaluated in a number of other countries.<ref>{{cite web|title=Celgene Biopharmaceutical - Investor relations - Press Releases|url=http://ir.celgene.com/phoenix.zhtml?c=111960&p=irol-newsArticle&ID=1707228|archive-url=https://archive.today/20130119071315/http://ir.celgene.com/phoenix.zhtml?c=111960&p=irol-newsArticle&ID=1707228|url-status=dead|archive-date=19 January 2013|access-date=18 September 2012}}</ref><ref>{{cite web|title=Revlimid (lenalidomide) dosing, indications, interactions, adverse effects, and more|url=http://reference.medscape.com/drug/revlimid-lenalidomide-342200|publisher=Medscape references|access-date=18 September 2012}}</ref>
Numerous clinical trials are already in the pipeline or being conducted to explore further use for lenalidomide, alone or in combination with other drugs. Some of these indications include [[acute myeloid leukemia]], [[follicular lymphoma]], [[MALT lymphoma]], [[Waldenström's macroglobulinemia|Waldenström macroglobulinemia]], [[lupus erythematosus]], [[Hodgkin's lymphoma]], myelodysplastic syndrome and more.<ref>{{cite web|title=Search of: lenalidomide - List Results|url=http://clinicaltrials.gov/ct2/results?term=lenalidomide&pg=1|publisher=Clinical Trials|access-date=18 September 2012}}</ref><ref>{{cite web|title=Clinical Trials Register|url=https://www.clinicaltrialsregister.eu/ctr-search/search?query=lenalidomide|publisher=EU Clinical Trials Register|access-date=18 September 2012}}</ref>
===Pomalidomide===
Pomalidomide was submitted for FDA approval on April 26, 2012<ref>{{cite web|title=Celgene Submits Pomalidomide For FDA Approval|url=http://www.myelomabeacon.com/news/2012/04/26/celgene-submits-pomalidomide-for-fda-approval|publisher=The myeloma beacon}}</ref> and on 21 June it was announced that the drug would get standard FDA review. A marketing authorization application was filed to EMA 21 June 2012, where a decision could come as soon as early 2013. EMA has already granted pomalidomide an orphan designation for primary [[myelofibrosis]], MM, [[Systemic scleroderma|systemic sclerosis]], post-[[Polycythemia vera|polycythaemia]] and post-essential thrombocythaemia myelofibrosis.<ref>{{cite web|title=European Medicines Agency - Search results from your query|url=http://www.ema.europa.eu/ema/index.jsp?curl=search.jsp&q=pomalidomide&btnG=Search&mid=|publisher=European Medicines Agency|access-date=18 September 2012|archive-date=5 March 2016|archive-url=https://web.archive.org/web/20160305014221/http://www.ema.europa.eu/ema/index.jsp?curl=search.jsp&q=pomalidomide&btnG=Search&mid=|url-status=dead}}</ref>
==Adverse effects==
The major toxicities of approved IMiDs are [[peripheral neuropathy]], [[thrombocytopenia]], [[anaemia]] and [[venous thromboembolism]].<ref name = Haem2012/> There may be an increased risk of secondary malignancies, especially [[acute myeloid leukaemia]] in those receiving IMiDs.<ref name = Haem2012/>
===Teratogenicity===
Thalidomide's teratogenicity has been a subject of much debate and over the years numerous [[hypothesis|hypotheses]] have been proposed. Two of the best-known have been the anti-angiogenesis hypothesis and oxidative stress model hypothesis, with considerable experimental evidence supporting these two hypotheses regarding thalidomide's teratogenicity.<ref name=Ito2012>{{cite journal|last=Ito|first=Takumi|author2=Handa, Hiroshi|title=Deciphering the mystery of thalidomide teratogenicity|journal=Congenital Anomalies|date=1 March 2012|volume=52|issue=1|pages=1–7|doi=10.1111/j.1741-4520.2011.00351.x|pmid=22348778|doi-access=free}}</ref>
Recently, new findings have emerged that suggest a novel mechanism of teratogenicity. [[Cereblon]] is a 51 k[[Dalton (unit)|Da]] protein localized in the [[cytoplasm]], [[cell nucleus|nucleus]] and peripheral membrane of cells in numerous parts of the body.<ref name=Mariniani2012 /> It acts as a component of the [[Ubiquitin ligase|E3 ubiquitin ligase]], regulating various developmental processes, including [[embryogenesis]], [[carcinogenesis]] and cell cycle regulation, through degradation ([[Ubiquitination#Ubiquitination (ubiquitylation)|ubiquitination]]) of unknown substrates. Thalidomide has been shown to bind to cereblon, inhibiting the activity of the E3 ubiquitin ligase, resulting in accumulation of the ligase substrates and downregulation of [[FGF8|fibroblast growth factor 8]] (FGF8) and [[FGF10]]. This disrupts the [[positive feedback loop]] between the two growth factors, possibly causing both multiple birth defects and anti-myeloma effects.
Findings also support the hypothesis that an increase in the expression of cereblon is an essential element of the anti-myeloma effect of both lenalidomide and pomalidomide.<ref name=Ito2012 /> Cereblon expression was three times higher in responding patients compared to non-responders and higher cereblon expression was also associated with partial or full response while lower expression was associated with stable or progressive disease.<ref name=Mariniani2012 />
==Mechanism of action==
Their mechanism of action is not entirely clear, but it is known that they inhibit the production of [[tumour necrosis factor]], [[interleukin 6]] and [[immunoglobulin G]] and [[vascular endothelial growth factor|VEGF]] (which leads to its anti-angiogenic effects), co-stimulates [[T
Thalidomide and its analogs, lenalidomide and pomalidomide, are believed to act in a similar fashion even though their exact [[mechanism of action]] is not yet fully understood. It is believed that they work through different mechanisms in various diseases. The net effect is probably due to different mechanisms combined. Mechanism of action will be explained in light of today's knowledge.
===Thalidomide, lenalidomide and pomalidomide===
[[File:TLP-MOA.png|thumb|500px|right|alt=Mechanism of action|'''Figure 2:''' The mechanism of TLP in multiple myeloma. TLP refers to thalidomide, lenalidomide and pomalidomide]]
====Altering cytokine production====
Thalidomide and its immune-modulating analogs alter the production of the inflammatory cytokines TNF-α, [[Interleukin 1 family|IL-1]], [[interleukin 6|IL-6]], [[interleukin 12|IL-12]] and anti-inflammatory cytokine [[interleukin 10|IL-10]].<ref name=Mariniani2012>{{cite journal|last=Martiniani|first=Roberta|author2=Di Loreto, Valentina |author3=Di Sano, Chiara |author4=Lombardo, Alessandra |author5=Liberati, Anna Marina |title=Biological Activity of Lenalidomide and Its Underlying Therapeutic Effects in Multiple Myeloma|journal=Advances in Hematology|date=1 January 2012|volume=2012|pages=842945|doi=10.1155/2012/842945|pmid=22919394|pmc=3417169|doi-access=free}}</ref> The analogs are believed to inhibit the production of TNF-α, where the analogs are up to 50.000 times more potent ''in vitro'' than the parent drug thalidomide.<ref name=Huang2008>{{cite journal|last=Huang|first=Yen-Ta|author2=Hsu, Chih W. |author3=Chiu, Ted H. |title=Thalidomide and Its Analogs as Anticancer Agents|journal=Tzu Chi Medical Journal|date=1 September 2008|volume=20|issue=3|pages=188–195|doi=10.1016/S1016-3190(08)60034-8|doi-access=free}}</ref> The mechanism is believed to be through enhanced degradation of TNF-α [[mRNA]], resulting in diminished amounts of this pro-inflammatory cytokine secreted.<ref name=Melchert2007 /> This explains the effect of thalidomide when given to ENL patients, as they commonly have high levels of TNF-α in their blood and in dermatological lesions.<ref name=Bartlett2004 /> In contrast, ''in vitro'' assay demonstrated that TNF-α is actually enhanced in T-cell activation, where [[CD4|CD4+]] and [[CD8|CD8+]] T lymphocytes were stimulated by anti-CD3<ref name=Bartlett2004 /><ref name=Huang2008 /> which was later confirmed in an early phase trials involving [[solid tumors]] and inflammatory dermatologic diseases.<ref name=Melchert2007>{{cite journal|last=Melchert|first=Magda|author2=List, Alan|title=The thalidomide saga|journal=The International Journal of Biochemistry & Cell Biology|date=1 July 2007|volume=39|issue=7–8|pages=1489–1499|doi=10.1016/j.biocel.2007.01.022|pmid=17369076}}</ref>
[[Interleukin 12|IL-12]] is another cytokine both suppressed and enhanced by thalidomide and its analogs. When monocytes are stimulated by [[lipopolysaccharide]]s, IL-12 production is suppressed but during [[T cell activation|T-cell stimulation]] the production is enhanced.<ref name=Huang2008 />
Lenalidomide is believed to be about 1000 times more potent ''in vitro'' than thalidomide in anti-inflammatory properties and pomalidomide about 10 times more potent than lenalidomide. It is worth noticing however that, when comparing lenalidomide and pomalidomide, clinical relevance of higher in vitro potency is unclear since [[maximum tolerated dose]] of pomalidomide is 2 mg daily compared to 25 mg for lenalidomide, leading to 10-100 times lower plasma drug concentration of pomalidomide.<ref name=Quach2009>{{cite journal|last=Quach|first=H|author2=Ritchie, D |author3=Stewart, A K |author4=Neeson, P |author5=Harrison, S |author6=Smyth, M J |author7= Prince, H M |title=Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma|journal=Leukemia|date=12 November 2009|volume=24|issue=1|pages=22–32|doi=10.1038/leu.2009.236 |pmid=19907437 |pmc=3922408}}</ref>
====T-cell activation====
Thalidomide and its analogs help with the co-stimulation of T-cells through the [[B7 (protein)|B7]]-[[CD28]] complex by phosphorylating [[tyrosine]] on the CD28 receptor.<ref name=Bartlett2004 /> ''In vitro'' data suggests this co-stimulation leads to increased [[Th1 cell|Th1]] type cytokine release of IFN-γ and IL-2 that further stimulates clonal T cell proliferation and [[natural killer cell]] proliferation and activity. This enhances natural and antibody dependent cellular [[cytotoxicity]].<ref name=Thomas2007>{{cite journal|last=Thomas|first=Sheeba K.|author2=Richards, Tiffany A. |author3=Weber, Donna M. |title=Lenalidomide in multiple myeloma|journal=Best Practice & Research Clinical Haematology|date=1 December 2007|volume=20|issue=4|pages=717–735|doi=10.1016/j.beha.2007.09.002|pmid=18070715}}</ref> Lenalidomide and pomalidomide are about 100-1000 times more potent in stimulating T-cell clonal proliferation than thalidomide. In addition, ''in vitro'' data suggests pomalidomide reverts [[Th2]] cells into Th1 by enhancing transcription factor [[TBX21|T-bet]].<ref name=Mariniani2012 />
====Anti-angiogenesis====
Angiogenesis or the growth of new blood vessels has been reported to correspond with MM progression where [[vascular endothelial growth factor]] (VEGF) and its receptor, [[bFGF]]<ref name=Bartlett2004 /> and IL-6<ref name=Huang2008 /> appear to be required for endothelial cell migration during angiogenesis. Thalidomide and its analogs are believed to suppress angiogenesis through modulation of the above-mentioned factors where potency in anti-angiogenic activity for lenalidomide and pomalidomide was 2-3 times higher than for thalidomide in various ''[[in vivo]]'' assays,<ref name=Kotla2009>{{cite journal|last=Kotla|first=Venumadhav|author2=Goel, Swati |author3=Nischal, Sangeeta |author4=Heuck, Christoph |author5=Vivek, Kumar |author6=Das, Bhaskar |author7= Verma, Amit |title=Mechanism of action of lenalidomide in hematological malignancies|journal=Journal of Hematology & Oncology|date=1 January 2009|volume=2|issue=1|page=36|doi=10.1186/1756-8722-2-36 |pmid=19674465 |pmc=2736171 |doi-access=free }}</ref> Thalidomide has also been shown to block [[NF-κB]] activity through the blocking of IL-6, and NF-κB has been shown to be involved in angiogenesis.<ref name=Huang2008 /> Inhibition of TNF-α is not the mechanism of thalidomide's inhibition of angiogenesis since numerous other TNF-α inhibitors do not inhibit angiogenesis.<ref name="ncbi.nlm.nih.gov"/>
====Anti-tumor activity====
''In vivo'' anti-tumor activity of thalidomide is believed to be due to the potent anti-angiogenic effect and also through changes in cytokine expression. ''In vitro'' assays on [[apoptosis]] in MM cells have been shown, when treated with thalidomide and its analogs, to upregulate the activity of [[caspase-8]]. This causes cross talking of apoptotic signaling between caspase-8 and [[caspase-9]] leading to indirect upregulation of caspase-9 activity.<ref name=Mariniani2012 /><ref name=Melchert2007 /> Further anti-tumor activity is mediated through the inhibition of apoptosis protein-2<ref name=Kotla2009 /> and pro-survival effects of [[Insulin-like growth factor 1|IGF-1]], increasing sensitivity to [[Fas ligand#Cell signaling|FAS mediated cell death]] and enhancement of [[TRAIL|TNF-related apoptosis inducing ligand]].<ref name=Melchert2007 /> They have also been shown to cause dose dependent [[G0 phase|G0]]/[[G1 phase|G1]] [[cell cycle]] arrest in leukemia cell lines<ref name=Huang2008 /> where the analogs showed 100 times more potency than thalidomide.<ref name=Quach2009 />
====Bone marrow environment====
The role of angiogenesis in the support of myeloma was first discovered by Vacca in 1994.<ref>{{cite journal |pmid = 7527645 | volume=87 | issue=3 | title=Bone marrow angiogenesis and progression in multiple myeloma |date=July 1994 |vauthors=Vacca A, Ribatti D, Roncali L, etal | journal=Br. J. Haematol. | pages=503–8 | doi=10.1111/j.1365-2141.1994.tb08304.x| pmc=3301416 }}</ref> They discovered increased bone marrow angiogenesis correlates with myeloma growth and supporting stromal cells are a significant source for angiogenic molecules in myeloma. This is believed to be a main component of the mechanism ''in vivo'' by which thalidomide inhibits multiple myeloma.
Additionally, inflammatory responses within the bone marrow are believed to foster many hematological diseases. The secretion of IL-6 by [[bone marrow]] [[stromal cells]] (BMSC) and the secretion of the adhesion molecules [[VCAM-1]], [[ICAM-1]] and [[Lymphocyte function-associated antigen 1|LFA]], is induced in the presence of TNF-α and the adhesion of MM cells to BMSC. In vitro proliferation of MM cell lines and inhibition of Fas-mediated apoptosis is promoted by IL-6.<ref name=Melchert2007 /> Thalidomide and its analogs directly decrease the up-regulation of IL-6 and indirectly through TNF-α, thereby reducing the secretion of adhesion molecules leading to fewer MM cells adhering to BMSC. [[Osteoclast]]s become highly active during MM, leading to [[bone resorption]] and secretion of various MM survival factors. They decrease the levels of [[Cell adhesion molecule|adhesion molecules]] paramount to osteoclast activation, decrease the formation of the cells that form osteoclasts and downregulate [[cathepsin K]], an important [[cysteine protease]] expressed in osteoclasts.<ref name=Kotla2009 />
==Structure-activity relationship==
[[File:Thalidomide numbering and ring system.svg|thumb|250px|'''Figure 5:''' Thalidomide with the ring system outlined]]
Since the mechanism of action of thalidomide and its analogs is not fully clear and the bioreceptor for these substances has not been identified, the insight into the relationship between the structure and activity of thalidomide and its analogs are mostly derived from [[molecular modelling]] and continued research investigation.<ref name=Man2003 /><ref name=Avila2006>{{cite journal|last=Avila|first=Carolina Martins|author2=Romeiro, Nelilma Correia |author3=Sperandio da Silva, Gilberto M. |author4=Sant’Anna, Carlos M.R. |author5=Barreiro, Eliezer J. |author6=Fraga, Carlos A.M. |title=Development of new CoMFA and CoMSIA 3D-QSAR models for anti-inflammatory phthalimide-containing TNFα modulators|journal=Bioorganic & Medicinal Chemistry|date=1 October 2006|volume=14|issue=20|pages=6874–6885|doi=10.1016/j.bmc.2006.06.042 |pmid=16843662}}</ref>
The information on SAR of thalidomide and its analogs is still in process so any trends detailed here are observed during individual studies.
Research has mainly focused on improving the TNF-α and PDE4 inhibition of thalidomide,<ref name=Bartlett2004 /><ref name=Man2009 /> as well as the anti-angiogenesis activity.<ref name=Lepper2004>{{cite journal|last=Lepper|first=Erin R.|author2=Ng, Sylvia S. W. |author3=Gütschow, Michael |author4=Weiss, Michael |author5=Hauschildt, Sunna |author6=Hecker, Thomas K. |author7=Luzzio, Frederick A. |author8=Eger, Kurt |author9= Figg, William D. |title=Comparative Molecular Field Analysis and Comparative Molecular Similarity Indices Analysis of Thalidomide Analogues as Angiogenesis Inhibitors|journal=Journal of Medicinal Chemistry|date=1 April 2004|volume=47|issue=9|pages=2219–2227|doi=10.1021/jm0304820|pmid=15084120}}</ref><ref name=Noguchi2005>{{cite journal|last=Noguchi|first=Tomomi|author2=Fujimoto, Haruka |author3=Sano, Hiroko |author4=Miyajima, Atsushi |author5=Miyachi, Hiroyuki |author6= Hashimoto, Yuichi |title=Angiogenesis inhibitors derived from thalidomide|journal=Bioorganic & Medicinal Chemistry Letters|date=1 December 2005|volume=15|issue=24|pages=5509–5513|doi=10.1016/j.bmcl.2005.08.086|pmid=16183272}}</ref>
===TNF-α inhibitors (not via PDE4)===
Research indicated that a substitution at the phthaloyl ring would increase TNF-α inhibition activity (Figure 5). An amino group substitution was tested at various locations on the phthaloyl ring (C4, C5, C6, C7) of thalidomide and EM-12 (previously described). Amino addition at the C4 location on both thalidomide and EM-12 resulted in much more potent inhibition of TNF-α. This also revealed that the amino group needed to be directly opposite the carbonyl group on the isoindolinone ring system for the most potent activity.<ref name=Muller1999>{{cite journal|last=Muller|first=GW|author2=Chen, R |author3=Huang, SY |author4=Corral, LG |author5=Wong, LM |author6=Patterson, RT |author7=Chen, Y |author8=Kaplan, G |author9= Stirling, DI |title=Amino-substituted thalidomide analogs: potent inhibitors of TNF-alpha production.|journal=Bioorganic & Medicinal Chemistry Letters|date=Jun 7, 1999|volume=9|issue=11|pages=1625–30|pmid=10386948|doi=10.1016/s0960-894x(99)00250-4}}</ref> These analogs do not inhibit PDE4 and therefore do not act by PDE4 inhibition. Other additions of longer and bigger groups at the C4 and C5 position of the phthaloyl ring system of thalidomide, some with an [[olefin]] functionality, have been tested with various results. Increased inhibitory effect, compared to thalidomide, was noticed with the groups that had an oxygen atom attached directly to the C5 or C4 olefin. [[Iodine]] and [[bromine]] addition at C4 or C5 resulted in equal or decreased activity compared to thalidomide.<ref name=Stewart2007>{{cite journal|last=Stewart|first=Scott G.|author2=Spagnolo, Daniel |author3=Polomska, Marta E. |author4=Sin, Melvin |author5=Karimi, Mahdad |author6= Abraham, Lawrence J. |title=Synthesis and TNF expression inhibitory properties of new thalidomide analogues derived via Heck cross coupling|journal=Bioorganic & Medicinal Chemistry Letters|date=1 November 2007|volume=17|issue=21|pages=5819–5824|doi=10.1016/j.bmcl.2007.08.042 |pmid=17851074}}</ref> These groups were not compared with lenalidomide or pomalidomide.
===PDE4 inhibitors===
[[File:Rolipram with 3,4-dialkoxyphenyl moiety highlighted.svg|thumb|right|250px|'''Figure 6:''' Rolipram, highlighting the 3,4-dialkoxyphenyl moiety]]
[[File:PDE4-inhibiting thalidomide analogs.svg|thumb|right|250px|'''Figure 7:''' Common structure for PDE4-inhibiting thalidomide analogs]]
The common structure for analogs that inhibit TNF-α via inhibition of PDE4 is prepared on the basis of hydrolysing the glutarimide ring of thalidomide. These analogs do not have an acidic chiral hydrogen, unlike thalidomide, and would therefore be expected to be chirally stable.<ref name=Muller1996 />
On the phenyl ring, a 3,4-dialkoxyphenyl moiety (Figure 6) is a known pharmacophore in PDE4 inhibitors such as [[rolipram]]. Optimal activity is achieved with a methoxy group at the 4-position (X2) and a bigger group, such as cyclopentoxy at the 3-position carbon (X3). However the thalidomide PDE4 inhibitory analogs do not follow the SAR of rolipram analogs directly. For thalidomide analogs, an ethoxy group at X3 and a methoxy group at X2, with X1 being just a hydrogen, gave the highest PDE4 and TNF-α inhibition.<ref name=Man2009 /> Substitutes larger than diethoxy at the X2–X3 position had decreased activity. The effects of these substitutions seem to be mediated by steric effects.<ref name=Muller1996 />
For the Y-position, a number of groups have been explored. Substituted amides that were larger than [[methylamide]] (CONHCH<sub>3</sub>) decrease PDE4 inhibition activity.<ref name=Muller1996 /> Using a carboxylic acid as a starting point, an amide group has similar PDE4 inhibition activity but both groups were shown to be a considerably less potent than a methyl ester group, which had about six-fold increase in PDE4 inhibitory activity. Sulfone group had similar PDE4 inhibition as the methyl ester group. The best PDE4 inhibition was observed when a nitrile group was attached, which has 32 times more PDE4 inhibitory activity than the carboxyl acid.<ref name=Man2009 /> Substituents at Y leading to increasing PDE4 inhibitory activity thus followed the order:
: COOH ≤ CONH<sub>2</sub> ≤ COOCH<sub>3</sub> ≤ SO<sub>2</sub>CH<sub>3</sub> < CN
Substitutions on the phthaloyl ring have been explored and it was noticed that nitro groups at the C4 or C5 location decreased activity but C4 or C5 amino substitution increased it dramatically.<ref name=Muller1996 /> When the substitution at the 4 (Z) location on the phthaloyl ring was examined, hydroxyl and methoxy groups seem to make the analog a less potent PDE4 inhibitor. An increase in activity was observed with amino and dimethylamino to a similar extent but a methyl group improved the activity further than the aforementioned groups. A 4-''N''-acetylamino group had slightly lower PDE4 inhibitory activity, compared with the methyl group, but increased the compound's TNF-α inhibitory activity to a further extent.<ref name=Man2009 /> Substituents at Z leading to increasing PDE4 inhibitory activity thus followed the order:
: N(CH<sub>3</sub>)<sub>2</sub> ≤ NH<sub>2</sub> < NHC(O)CH<sub>3</sub> < CH<sub>3</sub>
===Angiogenesis inhibition===
[[File:Angiogenesis-inhibiting thalidomide analogs.svg|thumb|250px|right|'''Figure 8:''' Common structure for thalidomide analogs with angiogenesis inhibition]]
For angiogenesis inhibition activity, an intact [[glutarimide]] ring seems to be required. Different groups were tested in the R position. The substances that had nitrogen salts as the R group showed good activity. The improved angiogenesis inhibitory activity could be due to increased solubility or that the positively charged nitrogen has added interaction with the active site. Tetrafluorination of the phthaloyl ring seems to increase the angiogenesis inhibition.<ref name=Lepper2004 />
==Synthesis==
{{Technical|section|date=April 2017}}
Described below are schemes for [[Organic synthesis|synthesizing]] thalidomide, lenalidomide, and pomalidomide, as reported from prominent [[primary literature]]. Note that these synthesis schemes do not necessarily reflect the organic synthesis strategies used to synthesize these single chemical entities.
===Thalidomide===
[[File:Thalidomide synthesis 1.png|thumb|center|500px|'''Scheme 1:''' Thalidomide synthesis, the older procedure]]
[[File:Thalidomide synthesis 2.png|thumb|center|500px|'''Scheme 2:''' Newer thalidomide synthesis, two step reaction]]
Synthesis of thalidomide has usually been performed as seen in scheme 1. This synthesis is a reasonably simplistic three step process. The downside of this process however is that the last step requires a high-temperature melt reaction which demands multiple [[Recrystallization (chemistry)|recrystallizations]] and is not compliant with standard equipment.
Scheme 2 is the newer synthesis route which was designed to make the reaction more direct and to produce better yields. This route uses [[Glutamine|<small>L</small>-glutamine]] rather than [[Glutamic acid|<small>L</small>-glutamic acid]] as a starting material and by letting it react with ''N''-carbethoxyphthalimide gives ''N''-phthaloyl-<small>L</small>-glutamine (4), with 50–70% yield. The substance 4 is then stirred in a mixture with carbonyldiimidazole ([[Carbonyldiimidazole|CDI]]) with enough 4-dimethylaminopyridine ([[4-Dimethylaminopyridine|DMAP]]) in tetrahydrofuran ([[Tetrahydrofuran|THF]]) to catalyze the reaction and heated to [[reflux]] for 15–18 hours. During the reflux thalidomide crystallizes out of the mixture. The final step gives 85–93% yield of thalidomide, bringing the total yield to 43–63%.<ref name=MullerKonnecke1999>{{cite journal|last=Muller|first=George W.|author2=Konnecke, William E. |author3=Smith, Alison M. |author4= Khetani, Vikram D. |title=A Concise Two-Step Synthesis of Thalidomide|journal=Organic Process Research & Development|date=1 March 1999|volume=3|issue=2|pages=139–140|doi=10.1021/op980201b}}</ref>
===Lenalidomide and pomalidomide===
[[File:Pomalidomide synthesis.png|thumb|center|500px|'''Scheme 3:''' Pomalidomide synthesis]]
Both of the amino analogs are prepared from the condensation of 3-aminopiperidine-2,6-dione hydrochloride (Compound 3) which is synthesized in a two step reaction from commercially available [[Carboxybenzyl|Cbz]]-<small>L</small>-glutamine. The Cbz-<small>L</small>-glutamine is treated with CDI in refluxing THF to yield Cbz-aminoglutarimide. To remove the Cbz protecting group [[hydrogenolysis]], under 50–60 [[Pounds per square inch|psi]] of hydrogen with 10% [[Palladium on carbon|Pd/C]] mixed with [[ethyl acetate]] and HCl, was performed. The formulated hydrochloride (Compound 3 in Scheme 3) was then reacted with 3-nitrophthalic anhydride in refluxing acetic acid to yield the 4-nitro substituted thalidomide analog and the nitro group then reduced with [[hydrogenation]] to give pomalidomide.<ref name=Muller1999 />
[[File:Lenalidomide synthesis.png|thumb|center|600px|'''Scheme 4:''' Lenalidomide synthesis]]
Lenalidomide is synthesized in a similar way using compound 3 (3-aminopiperidine-2,6-dione) treated with a nitro-substituted methyl 2-(bromomethyl) benzoate, and hydrogenation of the nitro group.<ref name=Muller1999 />
==Pharmacokinetics==
===Thalidomide===
{{Main|Thalidomide}}
{| class="wikitable" style="margin:auto;"
|-
!colspan="3"|Thalidomide
|-
| '''T<sub>max</sub> [drug]'''
| 4–6 hours in subjects with MM<ref name=Chung2004>{{cite journal|last=Chung|first=F.|title=Thalidomide Pharmacokinetics and Metabolite Formation in Mice, Rabbits, and Multiple Myeloma Patients|journal=Clinical Cancer Research|date=1 September 2004|volume=10|issue=17|pages=5949–5956|doi=10.1158/1078-0432.CCR-04-0421|pmid=15355928|doi-access=free}}</ref> <br />
|rowspan="4"|[[Image:Thalidomide.svg|200px]]
|-
| '''Protein binding'''
| 55–65%<ref name=ThalidomidSmPC>{{cite web|title=Summary of product characteristics: Thalidomid Celgene|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000823/WC500037050.pdf|publisher=European Medicines Agency|access-date=23 September 2012}}</ref>
|-
|'''Metabolites'''
| Hydrolized metabolites<ref name=ThalidomidSmPC />
|-
|'''Half-life [t<sub>1/2</sub>]'''
|5.5–7.6 hours<ref name=ThalidomidSmPC />
|}
===Lenalidomide===
{{Main|Lenalidomide}}
{| class="wikitable" style="margin:auto;"
|-
!colspan="3"|Lenalidomide
|-
| '''T<sub>max</sub> [drug]'''
|0.6–1.5 hours in healthy subjects<ref name=Armoiry2008>{{cite journal|last=Armoiry|first=X.|author2=Aulagner, G. |author3=Facon, T. |title=Lenalidomide in the treatment of multiple myeloma: a review|journal=Journal of Clinical Pharmacy and Therapeutics|date=1 June 2008|volume=33|issue=3|pages=219–226|doi=10.1111/j.1365-2710.2008.00920.x|pmid=18452408|doi-access=free}}</ref><br />
0.5–4 hours in subjects with MM<ref name=Richardson2002>{{cite journal|last=Richardson|first=P. G.|title=Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma|journal=Blood|date=12 July 2002|volume=100|issue=9|pages=3063–3067|doi=10.1182/blood-2002-03-0996|pmid=12384400|doi-access=free}}</ref>
|rowspan="4"|[[Image:Lenalidomide.svg|200px|Lenalidomide]]
|-
| '''Protein binding'''
| ~30%<ref name=Armoiry2008 />
|-
|'''Metabolites'''
|Has not yet been studied<ref name=Armoiry2008 />
|-
|'''Half-life [t<sub>1/2</sub>]'''
|3 hours in healthy subjects<ref name=Armoiry2008 /><br />3.1–4.2 hours in subjects with MM<ref name=Richardson2002 />
|}
===Pomalidomide===
{{Main|Pomalidomide}}
{| class="wikitable" style="margin:auto;"
|-
!colspan="3"|Pomalidomide
|-
| '''T<sub>max</sub> [drug]'''
|0.5–8 hours<ref name=Schey2004>{{cite journal|last=Schey|first=S.A.|title=Phase I Study of an Immunomodulatory Thalidomide Analog, CC-4047, in Relapsed or Refractory Multiple Myeloma|journal=Journal of Clinical Oncology|date=15 August 2004|volume=22|issue=16|pages=3269–3276|doi=10.1200/JCO.2004.10.052|pmid=15249589|doi-access=free}}</ref><br />
|rowspan="4"|[[Image:Pomalidomide.svg|200px|Pomalidomide]]
|-
| '''Protein binding'''
| Unknown
|-
|'''Metabolites'''
| Unknown
|-
|'''Half-life [t<sub>1/2</sub>]'''
|6.2–7.9 hours<ref name=Schey2004 />
|}
==See also==
{{Div col|colwidth=22em}}
*[[Cancer]]
*[[Multiple myeloma]]
*[[Drug design]]
*[[Thalidomide]]
*[[Lenalidomide]]
*[[Pomalidomide]]
*[[Apremilast]]
*[[Organic chemistry]]
*[[Health crisis]]
*[[Immunomodulation therapy]]
*[[Immunosuppressant]]
*[[Immunomodulatory drug]]
{{div col end}}
==References==
{{
{{Immunosuppressants}}
{{Drug design}}
[[Category:Glutarimides]]
[[Category:Immunosuppressants]]
[[Category:Phthalimides]]
[[Category:Teratogens]]
[[Category:
[[Category:PDE4 inhibitors]]
[[Category:Orphan drugs]]
[[Category:TNF inhibitors]]
[[Category:Cereblon E3 ligase modulators]]
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