Optimising metabolic stability in lipophilic chemical space: the identification of a metabolically stable pyrazolopyrimidine CRF-1 receptor antagonist

Duncan C Miller; Wolfgang Klute; Andrew Calabrese; Alan D Brown

doi:10.1016/j.bmcl.2009.09.016

Optimising metabolic stability in lipophilic chemical space: the identification of a metabolically stable pyrazolopyrimidine CRF-1 receptor antagonist

Bioorg Med Chem Lett. 2009 Nov 1;19(21):6144-7. doi: 10.1016/j.bmcl.2009.09.016. Epub 2009 Sep 11.

Authors

Duncan C Miller¹, Wolfgang Klute, Andrew Calabrese, Alan D Brown

Affiliation

¹ Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. duncan.miller@pfizer.com

PMID: 19782566
DOI: 10.1016/j.bmcl.2009.09.016

Abstract

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.

MeSH terms

Animals
Humans
Ligands
Microsomes, Liver / metabolism
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / pharmacokinetics
Rats
Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
Receptors, Corticotropin-Releasing Hormone / metabolism
Structure-Activity Relationship

Substances

Ligands
Pyrimidines
Receptors, Corticotropin-Releasing Hormone
CRF receptor type 1