Synthesis and structure-activity relationships of N3-pyridylpyrazinones as corticotropin-releasing factor-1 (CRF1) receptor antagonists

Richard A Hartz; Vijay T Ahuja; William D Schmitz; Thaddeus F Molski; Gail K Mattson; Nicholas J Lodge; Joanne J Bronson; John E Macor

doi:10.1016/j.bmcl.2010.01.129

Synthesis and structure-activity relationships of N3-pyridylpyrazinones as corticotropin-releasing factor-1 (CRF1) receptor antagonists

Bioorg Med Chem Lett. 2010 Mar 15;20(6):1890-4. doi: 10.1016/j.bmcl.2010.01.129. Epub 2010 Feb 1.

Authors

Richard A Hartz¹, Vijay T Ahuja, William D Schmitz, Thaddeus F Molski, Gail K Mattson, Nicholas J Lodge, Joanne J Bronson, John E Macor

Affiliation

¹ Neuroscience Discovery Chemistry, Research and Development, Bristol-Myers Squibb Company, Wallingford, CT 06492, USA. [email protected]

PMID: 20176478
DOI: 10.1016/j.bmcl.2010.01.129

Abstract

A series of N(3)-pyridylpyrazinones was investigated as corticotropin-releasing factor-1 receptor antagonists. It was observed that the binding affinity of analogues containing a pyridyl group was influenced not only by the substitution pattern on the pyridyl group, but also by the pK(a) of the pyridyl nitrogen. Analogues containing a novel 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine group were among the most potent N(3)-pyridylpyrazinones synthesized. The synthesis and SAR of N(3)-pyridylpyrazinones is described herein.

MeSH terms

Pyrazines / chemical synthesis*
Pyrazines / chemistry
Pyrazines / pharmacology*
Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Pyrazines
Receptors, Corticotropin-Releasing Hormone
CRF receptor type 1