ABSTRACT
The design and synthesis of a new series of potent non-prostanoid IP receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) are described. Detailed profiling of a number of analogues resulted in the identification of 5c (ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the prostanoid receptor family and a more modest 30- to 50-fold selectivity over the EP3 receptor. In our hands, its potency and efficacy are comparable or superior to MRE269 (the active metabolite of the clinical compound NS-304) with respect to in vitro IP receptor dependent cAMP accumulation assays. 5c had an excellent PK profile across species. Enterohepatic recirculation most probably contributes to a concentration-time profile after oral administration in the cynomolgus monkey that showed a very low peak-to-trough ratio. Following the identification of an acceptable solid form, 5c was selected for further development for the treatment of PAH.
Subject(s)
Acetates/therapeutic use , Carbamates/therapeutic use , Hypertension, Pulmonary/drug therapy , Receptors, Prostaglandin/agonists , Acetates/pharmacokinetics , Administration, Oral , Animals , Biological Availability , Carbamates/pharmacokinetics , Drug Discovery , Rats , Structure-Activity RelationshipABSTRACT
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.
