title: Modification of a dihydropyrrolopyrimidine phosphoinositide 3-kinase (PI3K) inhibitor to improve oral bioavailability.
abstract: Phosphoinositide 3-kinase (PI3K) is activated in various human cancer cells and well known as a cancer therapy target. We previously reported a dihydropyrrolopyrimidine derivative as a highly potent PI3K inhibitor that has strong tumor growth inhibition in a xenograft model. In this report, we describe further optimization to improve its bioavailability.
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: Shinma
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: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D010539:Permeability; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D012995:Solubility
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C527741:pyrrolopyrimidine
keywords: Cancer; Liver microsomal stability; Molecular planarity; PI3K; Permeability; Pharmacokinetic profile; Solubility