Document Detail


Lead optimization of a dihydropyrrolopyrimidine inhibitor against phosphoinositide 3-kinase (PI3K) to improve the phenol glucuronic acid conjugation.
MedLine Citation:
PMID:  23265889     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Our lead compound for a phosphoinositide 3-kinase (PI3K) inhibitor (1) was metabolically unstable because of rapid glucuronidation of the phenol moiety. Based on structure-activity relationship (SAR) information and a FlexSIS docking simulation score, aminopyrimidine was identified as a bioisostere of phenol. An X-ray structure study revealed a hydrogen bonding pattern of aminopyrimidine derivatives. Finally, aminopyrimidine derivatives 33 showed strong tumor growth inhibition against a KPL-4 breast cancer xenograft model in vivo.
Authors:
Hatsuo Kawada; Hirosato Ebiike; Masao Tsukazaki; Mitsuaki Nakamura; Kenji Morikami; Kiyoshi Yoshinari; Miyuki Yoshida; Kotaro Ogawa; Nobuo Shimma; Takuo Tsukuda; Jun Ohwada
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-12-3
Journal Detail:
Title:  Bioorganic & medicinal chemistry letters     Volume:  -     ISSN:  1464-3405     ISO Abbreviation:  Bioorg. Med. Chem. Lett.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9107377     Medline TA:  Bioorg Med Chem Lett     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012. Published by Elsevier Ltd.
Affiliation:
Research Division, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. Electronic address: kawadahto@chugai-pharm.co.jp.
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