ABSTRACT
The design and synthesis of two closely related series of prostacyclin receptor agonist compounds that showed excellent human IP receptor potency and efficacy is described. Compounds from this series showed in vivo activity after SC dosing in the monocrotaline model of PAH in rat.
Subject(s)
Drug Discovery , Hypertension, Pulmonary/drug therapy , Receptors, Prostaglandin/agonists , Animals , Humans , Hypertension, Pulmonary/chemically induced , Monocrotaline , Platelet Aggregation/drug effects , Rats , Receptors, Prostaglandin/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.