title: 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.
abstract: 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.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. Electronic address: kawadahto@chugai-pharm.co.jp.
authors.forename: Hatsuo
authors.initials: H
authors.lastname: Kawada
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Hirosato
authors.initials: H
authors.lastname: Ebiike
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Tsukazaki
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Koyama
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Morikami
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yoshinari
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shimma
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Takuo
authors.initials: T
authors.lastname: Tsukuda
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Ohwada
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D064593:Heterografts; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012995:Solubility; D014867:Water / Q000737:chemistry*
chemical_list: D010671:Phenylurea Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014867:Water
keywords: Cancer; Molecular planarity; PI3K; Pharmacokinetic profile; SBDD; Solubility