Abstract |
Serotonin, which is stored in platelets and is released during thrombosis, activates platelets via the 5-HT(2A) receptor. 5-HT(2A) receptor inverse agonists thus represent a potential new class of antithrombotic agents. Our medicinal program began with known compounds that displayed binding affinity for the recombinant 5-HT(2A) receptor, but which had poor activity when tested in human plasma platelet inhibition assays. We herein describe a series of phenyl pyrazole inverse agonists optimized for selectivity, aqueous solubility, antiplatelet activity, low hERG activity, and good pharmacokinetic properties, resulting in the discovery of 10k ( APD791). 10k inhibited serotonin-amplified human platelet aggregation with an IC(50) = 8.7 nM and had negligible binding affinity for the closely related 5-HT(2B) and 5-HT(2C) receptors. 10k was orally bioavailable in rats, dogs, and monkeys and had an acceptable safety profile. As a result, 10k was selected further evaluation and advanced into clinical development as a potential treatment for arterial thrombosis.
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Authors | Yifeng Xiong, Bradley R Teegarden, Jin-Sun Karoline Choi, Sonja Strah-Pleynet, Marc Decaire, Honnappa Jayakumar, Peter I Dosa, Martin D Casper, Lan Pham, Konrad Feichtinger, Brett Ullman, John Adams, Diane Yuskin, John Frazer, Michael Morgan, Abu Sadeque, Weichao Chen, Robert R Webb, Daniel T Connolly, Graeme Semple, Hussien Al-Shamma |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 53
Issue 11
Pg. 4412-21
(Jun 10 2010)
ISSN: 1520-4804 [Electronic] United States |
PMID | 20455563
(Publication Type: Journal Article)
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Chemical References |
- APD791
- Benzamides
- Morpholines
- Pyrazoles
- Receptor, Serotonin, 5-HT2A
- Serotonin 5-HT2 Receptor Agonists
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Topics |
- Animals
- Arteries
(drug effects)
- Benzamides
(chemistry, metabolism, pharmacokinetics, pharmacology)
- Dogs
- Drug Discovery
(methods)
- Drug Inverse Agonism
- Female
- Humans
- Inhibitory Concentration 50
- Male
- Morpholines
(chemistry, metabolism, pharmacokinetics, pharmacology)
- Platelet Aggregation
(drug effects)
- Pyrazoles
(chemistry, metabolism, pharmacokinetics, pharmacology)
- Rats
- Receptor, Serotonin, 5-HT2A
(metabolism)
- Serotonin 5-HT2 Receptor Agonists
- Structure-Activity Relationship
- Substrate Specificity
- Thrombosis
(drug therapy, metabolism)
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