title: Discovery of potent, metabolically stable purine CRF-1 antagonists with differentiated binding kinetic profiles.
abstract: Optimisation of the potency of a bicyclic CRF antagonist whilst retaining metabolic stability is described. A core change and incorporation of metabolically stable lipophilic groups resulted in a further potency gain without increasing metabolic liability. Pharmacological investigation of binding kinetics led to the identification of compound 25, a sub-nanomolar CRF-1 antagonist with slow dissociation kinetics and an encouraging pharmacokinetic profile.
authors: Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. duncan.miller@pfizer.com
authors: Duncan C
authors: DC
authors: Miller
authors: Wolfgang
authors: W
authors: Klute
authors: Alan D
authors: AD
authors: Brown
mesh_terms: D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D011687:Purines / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats
chemical_list: D011687:Purines; D003346:Corticotropin-Releasing Hormone; C030985:purine