Tavapadon

Tavapadon
Clinical data
Other names	CVL-751; PF-6649751; PF-06649751
Routes of; administration	By mouth
Drug class	Dopamine receptor agonist
Identifiers
	IUPAC name (−)-(6Ξ)-1,5-dimethyl-6-(2-methyl-4-[(3-[trifluoromethyl]pyridin-2-yl)oxy]phenyl)pyrimidine-2,4(1H,3H)-dione;
CAS Number	1643489-24-0;
PubChem CID	86764100;
ChemSpider	48062699;
UNII	PT4P8MJP8L;
KEGG	D11431;
ChEMBL	ChEMBL3697617;
CompTox Dashboard (EPA)	DTXSID301337071 ;
Chemical and physical data
Formula	C19H16F3N3O3
Molar mass	391.350 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CC1=C(C=CC(=C1)OC2=C(C=CC=N2)C(F)(F)F)C3=C(C(=O)NC(=O)N3C)C;
	InChI InChI=1S/C19H16F3N3O3/c1-10-9-12(28-17-14(19(20,21)22)5-4-8-23-17)6-7-13(10)15-11(2)16(26)24-18(27)25(15)3/h4-9H,1-3H3,(H,24,26,27); Key:AKQXQLUNFKDZBN-UHFFFAOYSA-N;

Tavapadon (developmental code names CVL-751, PF-06649751) is a dopamine receptor agonist which is under development for the treatment of Parkinson's disease.^[2]^[3]^[4] It is under development by Cerevel Therapeutics, which acquired tavapadon from Pfizer in 2018.^[2] It is taken by mouth.^[1]

Tavapadon acts as a highly selective partial agonist of the dopamine D₁ receptor (K_i = 9 nM; IATooltip Intrinsic activity = 65%) and the dopamine D₅ receptor (K_i = 13 nM; IA = 81%).^[3]^[4]^[1] It has no significant affinity or functional activity at the D₂-like receptors (D₂, D₃, D₄) (K_i ≥ 4,870 to 6,720 nM).^[1] Tavapadon also shows biased agonism for G_s-coupled signaling at the D₁-like receptors.^[1]^[3]

As of April 2024, tavapadon is in phase 3 clinical trials for Parkinson's disease.^[2]

References

^ ^a ^b ^c ^d ^e Bezard E, Gray D, Kozak R, Leoni M, Combs C, Duvvuri S (2024). "Rationale and Development of Tavapadon, a D1/D5-Selective Partial Dopamine Agonist for the Treatment of Parkinson's Disease". CNS Neurol Disord Drug Targets. 23 (4): 476–487. doi:10.2174/1871527322666230331121028. PMC 10909821. PMID 36999711. Tavapadon is a highly selective partial agonist at D1 and D5 dopamine receptors, [52] with little to no functional activity at D2, D3, or D4 receptors in vitro (unpublished data). Assays measuring the displacement of radioligand binding in cell lines expressing recombinant human dopamine receptors have shown that tavapadon has a high affinity for both D1 (Ki = 9 nM) and D5 (Ki = 13 nM) (unpublished data). Conversely, tavapadon had a low affinity at D2 (Ki ≥ 6210 nM), D3 (Ki ≥ 6720 nM), and D4 (Ki ≥ 4870 nM) (unpublished data). [...] In vitro assays of functional activity have confirmed that tavapadon acts as a partial agonist by binding at D1 and D5 receptors, corresponding to 65% and 81% of dopamine's intrinsic activity, respectively, and inducing functional receptor activation, with half-maximal effective concentration (EC50) values of 19 nM and 17 nM (unpublished data).
^ ^a ^b ^c "Tavapadon - Cerevel Therapeutics". Adis Insight. Springer Nature Switzerland AG.
^ ^a ^b ^c Cerri S, Blandini F (December 2020). "An update on the use of non-ergot dopamine agonists for the treatment of Parkinson's disease". Expert Opinion on Pharmacotherapy. 21 (18): 2279–2291. doi:10.1080/14656566.2020.1805432. PMID 32804544. S2CID 221163451.
^ ^a ^b Hall A, Provins L, Valade A (January 2019). "Novel Strategies To Activate the Dopamine D₁ Receptor: Recent Advances in Orthosteric Agonism and Positive Allosteric Modulation". Journal of Medicinal Chemistry. 62 (1): 128–140. doi:10.1021/acs.jmedchem.8b01767. PMID 30525590. S2CID 54469910.

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[BezardGrayKozak2024-1] Bezard E, Gray D, Kozak R, Leoni M, Combs C, Duvvuri S (2024). "Rationale and Development of Tavapadon, a D1/D5-Selective Partial Dopamine Agonist for the Treatment of Parkinson's Disease". CNS Neurol Disord Drug Targets. 23 (4): 476–487. doi:10.2174/1871527322666230331121028. PMC 10909821. PMID 36999711. Tavapadon is a highly selective partial agonist at D1 and D5 dopamine receptors, [52] with little to no functional activity at D2, D3, or D4 receptors in vitro (unpublished data). Assays measuring the displacement of radioligand binding in cell lines expressing recombinant human dopamine receptors have shown that tavapadon has a high affinity for both D1 (Ki = 9 nM) and D5 (Ki = 13 nM) (unpublished data). Conversely, tavapadon had a low affinity at D2 (Ki ≥ 6210 nM), D3 (Ki ≥ 6720 nM), and D4 (Ki ≥ 4870 nM) (unpublished data). [...] In vitro assays of functional activity have confirmed that tavapadon acts as a partial agonist by binding at D1 and D5 receptors, corresponding to 65% and 81% of dopamine's intrinsic activity, respectively, and inducing functional receptor activation, with half-maximal effective concentration (EC50) values of 19 nM and 17 nM (unpublished data).

[AdisInsight-2] "Tavapadon - Cerevel Therapeutics". Adis Insight. Springer Nature Switzerland AG.

[pmid32804544-3] Cerri S, Blandini F (December 2020). "An update on the use of non-ergot dopamine agonists for the treatment of Parkinson's disease". Expert Opinion on Pharmacotherapy. 21 (18): 2279–2291. doi:10.1080/14656566.2020.1805432. PMID 32804544. S2CID 221163451.

[pmid30525590-4] Hall A, Provins L, Valade A (January 2019). "Novel Strategies To Activate the Dopamine D₁ Receptor: Recent Advances in Orthosteric Agonism and Positive Allosteric Modulation". Journal of Medicinal Chemistry. 62 (1): 128–140. doi:10.1021/acs.jmedchem.8b01767. PMID 30525590. S2CID 54469910.

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[2]

[3]

[4]

See also

References