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.
Subject(s)
Arteries/drug effects , Benzamides/chemistry , Benzamides/pharmacology , Drug Discovery/methods , Drug Inverse Agonism , Morpholines/chemistry , Morpholines/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Serotonin 5-HT2 Receptor Agonists , Thrombosis/drug therapy , Animals , Benzamides/metabolism , Benzamides/pharmacokinetics , Dogs , Female , Humans , Inhibitory Concentration 50 , Male , Morpholines/metabolism , Morpholines/pharmacokinetics , Platelet Aggregation/drug effects , Pyrazoles/metabolism , Pyrazoles/pharmacokinetics , Rats , Receptor, Serotonin, 5-HT2A/metabolism , Structure-Activity Relationship , Substrate Specificity , Thrombosis/metabolismABSTRACT
A series of pyrimidine analogues derived from ATC0175 were potent antagonists of human MCH-R1 in vitro. Significantly improved receptor selectivity was achieved with several analogues from this series, but no improvement in brain partitioning was noted. One example from this series was shown to inhibit food intake and decrease body weight in a chronic study. However no clear correlation between the pharmacodynamic effect and the pharmacokinetic data with respect to brain concentration was discernible leading us to conclude that the observed effect was most likely not due to interaction with the MCH-R1.
Subject(s)
Anti-Obesity Agents/chemistry , Cyclohexylamines/chemistry , Pyrimidines/chemistry , Quinazolines/chemistry , Receptors, Somatostatin/antagonists & inhibitors , Administration, Oral , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacokinetics , Eating , Humans , Male , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptors, Somatostatin/metabolism , Structure-Activity Relationship , Weight LossABSTRACT
Potent 5-HT(2A) inverse-agonists containing phenyl-pyrazole ureas with an amino side chain were identified. Optimization of this series resulted in selective compounds that proved effective in modulating 5HT-induced amplification of ADP-stimulated human platelet aggregation.
Subject(s)
Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacology , Serotonin 5-HT2 Receptor Agonists , Urea/analogs & derivatives , Urea/pharmacology , Humans , Platelet Aggregation/drug effects , Pyrazoles/chemistry , Pyrazoles/pharmacology , Receptor, Serotonin, 5-HT2A/metabolism , Structure-Activity RelationshipABSTRACT
The optimization of a series of 4-(dimethylamino)quinazoline antagonists of the melanin-concentrating hormone receptor 1 (MCH-R1) is described. The combination of the elaboration of both the linker portion and the terminal phenyl ring provided N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difluorobenzamide hydrochloride 28 (ATC0175), which showed excellent antagonist activity at the MCH-R1 (IC50 = 3.4 nM) as well as good selectivity over the Y5 and the alpha2A receptors.
Subject(s)
Quinazolines/chemical synthesis , Receptors, Somatostatin/antagonists & inhibitors , Humans , Inhibitory Concentration 50 , Quinazolines/chemistry , Quinazolines/pharmacology , Radioligand Assay , Structure-Activity Relationship , Substrate SpecificityABSTRACT
A series of 4-(dimethylamino)quinazoline based antagonists of the melanin-concentrating hormone receptor 1 (MCH-R1) is described. This series was derived from a lead compound, AR129330, identified by HTS of a GPCR-directed library using a functional assay with a constitutively activated (CART) form of the receptor. The preliminary optimization resulted in the identification of compounds 20, 21, and 23.
