Document Detail


2-aryloxy-4-alkylaminopyridines: discovery of novel corticotropin-releasing factor 1 antagonists.
MedLine Citation:
PMID:  18288792     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Yuhpyng L Chen; R Scott Obach; John Braselton; Michael L Corman; James Forman; Jody Freeman; Randall J Gallaschun; Robert Mansbach; Anne W Schmidt; Jeffrey S Sprouse; F David Tingley Iii; Elizabeth Winston; David W Schulz
Publication Detail:
Type:  Journal Article     Date:  2008-02-21
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  51     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-03-06     Completed Date:  2008-06-05     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1385-92     Citation Subset:  IM    
Affiliation:
Medicinal Chemistry Department, Pfizer, Inc., Groton, Connecticut 06340, USA. yuhpyng888@yahoo.com
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MeSH Terms
Descriptor/Qualifier:
Action Potentials / drug effects
Administration, Oral
Adrenocorticotropic Hormone / blood
Aminopyridines / chemical synthesis*,  pharmacokinetics,  pharmacology
Animals
Antidepressive Agents / chemical synthesis*,  pharmacokinetics,  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
Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
Startle Reaction / drug effects
Structure-Activity Relationship
Chemical
Reg. No./Substance:
0/(3,6-dimethyl-2-(2,4,6-trimethylphenoxy)pyridin-4-yl)(1-ethylpropyl)amine; 0/Aminopyridines; 0/Antidepressive Agents; 0/CRF receptor type 1; 0/Receptors, Corticotropin-Releasing Hormone; 9002-60-2/Adrenocorticotropic Hormone; 9015-71-8/Corticotropin-Releasing Hormone

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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