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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
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]].
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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
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>
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===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==
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====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 />
====Anti-tumor activity====
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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
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| '''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]]
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[[Category:Teratogens]]
[[Category:Medicinal chemistry]]
[[Category:PDE4 inhibitors]]
[[Category:Orphan drugs]]
[[Category:TNF inhibitors]]
[[Category:Cereblon E3 ligase modulators]]
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