Synthesis and SAR of 2-aryloxy-4-alkoxy-pyridines as potent orally active corticotropin-releasing factor 1 receptor antagonists

A series of 2-aryloxy-4-alkoxy-pyridines (1) was identified as novel, selective, and orally active antagonists of the corticotropin-releasing factor 1 (CRF(1)) receptor. Among these, compound 2 (CP-316311) is a potent and selective CRF(1) receptor antagonist with an IC(50) value of 6.8 nM in receptor binding and demonstrates oral efficacy in central nervous system (CNS) in vivo models. The regiochemistry of compounds in this series was determined by an X-ray structural analysis. A method to control regioselectivity via pyridine-N-oxides was developed. The synthesis of compounds in series 1 (Figure 1) and [(3)H]-2 as well as the structure-activity relationship (SAR) are discussed. The in vitro, ex vivo, and in vivo properties of representative compounds are described herein. Compound 2 was advanced to phase II depression trials to test the hypothesis that CRF(1) antagonists could be used clinically as antidepressant drugs.