2-aryloxy-4-alkylaminopyridines: discovery of novel corticotropin-releasing factor 1 antagonists.
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.
Chen
Yuhpyng L
YL
Medicinal Chemistry Department, Pfizer, Inc., Groton, Connecticut 06340, USA. yuhpyng888@yahoo.com
Obach
R Scott
RS
Braselton
John
J
Corman
Michael L
ML
Forman
James
J
Freeman
Jody
J
Gallaschun
Randall J
RJ
Mansbach
Robert
R
Schmidt
Anne W
AW
Sprouse
Jeffrey S
JS
Tingley Iii
F David
FD
Winston
Elizabeth
E
Schulz
David W
DW
D000200:Action Potentials / Q000187:drug effects; D000284:Administration, Oral; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D004285:Dogs; D005215:Fasting; D006801:Humans; D007275:Injections, Intravenous; D008125:Locus Coeruleus / Q000502:physiology; D008297:Male; D010902:Pituitary Gland / Q000378:metabolism; D019518:Postprandial Period; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013216:Reflex, Startle / Q000187:drug effects; D013329:Structure-Activity Relationship; D000099052:CRF Receptor, Type 1
C529296:(3,6-dimethyl-2-(2,4,6-trimethylphenoxy)pyridin-4-yl)(1-ethylpropyl)amine; D000631:Aminopyridines; D000928:Antidepressive Agents; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone