Lead optimization of a dihydropyrrolopyrimidine inhibitor against phosphoinositide 3-kinase (PI3K) to improve the phenol glucuronic acid conjugation

H Kawada, H Ebiike, M Tsukazaki, M Nakamura…

Index: Kawada, Hatsuo; Ebiike, Hirosato; Tsukazaki, Masao; Nakamura, Mitsuaki; Morikami, Kenji; Yoshinari, Kiyoshi; Yoshida, Miyuki; Ogawa, Kotaro; Shimma, Nobuo; Tsukuda, Takuo; Ohwada, Jun Bioorganic and Medicinal Chemistry Letters, 2013 , vol. 23, # 3 p. 673 - 678

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Citation Number: 5

Abstract

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 ...