Optimization of the phenylurea moiety in a phosphoinositide 3-kinase (PI3K) inhibitor to improve water solubility and the PK profile by introducing a solubilizing group and ortho substituents

Publication date: 1 July 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
Author(s): Hatsuo Kawada, Hirosato Ebiike, Masao Tsukazaki, Shun Yamamoto, Kohei Koyama, Mitsuaki Nakamura, Kenji Morikami, Kiyoshi Yoshinari, Miyuki Yoshida, Kotaro Ogawa, Nobuo Shimma, Takuo Tsukuda, Jun Ohwada
Phosphoinositide 3-kinase (PI3K) is a promising anti-cancer target, because various mutations and amplifications are observed in human tumors isolated from cancer patients. Our dihydropyrrolopyrimidine derivative with a phenylurea moiety showed strong PI3K enzyme inhibitory activity, but its pharmacokinetic property was poor because of lack of solubility. Herein, we report how we improved the solubility of our PI3K inhibitors by introducing a solubilizing group and ortho substituents to break molecular planarity.

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