ABSTRACT
We have been exploring the potential of 5-HT(2B) antagonists as a therapy for chronic heart failure. To assess the potential of this therapeutic approach, we sought compounds possessing the following attributes: (a) potent and selective antagonism of the 5-HT(2B) receptor, (b) low impact of serum proteins on potency, and (c) desirable pharmacokinetic properties. This Letter describes our investigation of a biphenyl benzimidazole class of compounds that resulted in 5-HT(2B) antagonists possessing the above attributes. Improving potency in a human serum albumin shift assay proved to be the most significant SAR discovery.
Subject(s)
Receptor, Serotonin, 5-HT2B/metabolism , Serotonin 5-HT2 Receptor Antagonists , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacokinetics , Animals , Binding Sites , Male , Quantitative Structure-Activity Relationship , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptor, Serotonin, 5-HT2B/chemistry , Serotonin Antagonists/classificationABSTRACT
A novel series of pyrrolidine-1,2-dicarboxamides was discovered as factor Xa inhibitors using structure-based drug design. This series consisted of a neutral 4-chlorophenylurea P1, a biphenylsulfonamide P4 and a D-proline scaffold (1, IC(50) = 18 nM). Optimization of the initial hit resulted in an orally bioavailable, subnanomolar inhibitor of factor Xa (13, IC(50) = 0.38 nM), which was shown to be efficacious in a canine electrolytic model of thrombosis with minimal bleeding.