ABSTRACT
An orally active clinical candidate of corticotropin-releasing factor 1 (CRF 1) antagonist 1 showed a significant positive food effect in dog and human after oral administration. Efforts to address the food effect issue led us to explore and discover compounds in series 2 as orally active CRF 1 receptor antagonists, in which some compounds showed improved physicochemical properties while retaining desired pharmacological properties. Compound 3a (CP-376395) was selected for further development, due not only to its reduced food effects but also its greater efficacy in CNS models. Compound 3a was advanced to the clinic. The synthesis of representative potential candidates and their in vitro, ex vivo, and in vivo data are described.
Subject(s)
Aminopyridines/chemical synthesis , Antidepressive Agents/chemical synthesis , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Action Potentials/drug effects , Administration, Oral , Adrenocorticotropic Hormone/blood , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Animals , Antidepressive Agents/pharmacokinetics , Antidepressive Agents/pharmacology , Cerebral Cortex/metabolism , Corticotropin-Releasing Hormone/pharmacology , Dogs , Fasting , Humans , Injections, Intravenous , Locus Coeruleus/physiology , Male , Pituitary Gland/metabolism , Postprandial Period , Radioligand Assay , Rats , Rats, Sprague-Dawley , Reflex, Startle/drug effects , Structure-Activity RelationshipABSTRACT
The thiazole-diamide series (1) has been identified as highly potent gamma-secretase inhibitors. Several representative compounds showed IC(50) values of <0.3 nM. The synthesis and SAR, as well as a radiolabeled synthesis of [(3)H]-2a, are described.
