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Discovery of novel prostaglandin analogs as potent and selective EP2/EP4 dual agonists.
MedLine Citation:
PMID:  22386979     Owner:  NLM     Status:  Publisher    
To identify potent EP2/EP4 dual agonists with excellent subtype selectivity, a series of γ-lactam prostaglandin E analogs bearing a 16-phenyl ω-chain were synthesized and evaluated. Structural hybridization of 1 and 2, followed by more detailed chemical modification of the benzoic acid moiety, led us to the discovery of a 2-mercaptothiazole-4-carboxylic acid analog 3 as the optimal compound in the series. An isomer of this compound, the 2-mercaptothiazole-5-carboxylic acid analog 13, showed 34-fold and 13-fold less potent EP2 and EP4 receptor affinities, respectively. Structure activity relationship data from an in vitro mouse receptor binding assay are presented. Continued evaluation in an in vivo rat model of another 2-mercaptothiazole-4-carboxylic acid analog 17, optimized for sustained compound release from PLGA microspheres, demonstrated its effectiveness in a rat bone fracture-healing model following topical administration.
Tohru Kambe; Toru Maruyama; Yoshihiko Nakai; Hideyuki Yoshida; Hiroji Oida; Takayuki Maruyama; Nobutaka Abe; Akio Nishiura; Hisao Nakai; Masaaki Toda
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-2-16
Journal Detail:
Title:  Bioorganic & medicinal chemistry     Volume:  -     ISSN:  1464-3391     ISO Abbreviation:  -     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-3-5     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9413298     Medline TA:  Bioorg Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012. Published by Elsevier Ltd.
Minase Research Institute, Ono Pharmaceutical Co., Ltd., Shimamoto, Mishima, Osaka 618-8585, Japan.
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