Optimising metabolic stability in lipophilic chemical space: the identification of a metabolically stable pyrazolopyrimidine CRF-1 receptor antagonist.
Balancing potency and metabolic stability in a target which favours lipophilic ligands is a considerable challenge. Here we describe two strategies employed to achieve this balance in a series of pyrazolopyrimidine CRF antagonists: moderation of lipophilicity, and incorporation of a metabolically stable lipophilic group.
Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. duncan.miller@pfizer.com
Duncan C
DC
Miller
Wolfgang
W
Klute
Andrew
A
Calabrese
Alan D
AD
Brown
D000818:Animals; D006801:Humans; D008024:Ligands; D008862:Microsomes, Liver / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099052:CRF Receptor, Type 1
D008024:Ligands; D011743:Pyrimidines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1