Discovery of potent, metabolically stable purine CRF-1 antagonists with differentiated binding kinetic profiles
Duncan C Miller1, Wolfgang Klute, Alan D Brown
1Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. duncan.miller@pfizer.com
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.
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