title: Lead optimization of a dihydropyrrolopyrimidine inhibitor against phosphoinositide 3-kinase (PI3K) to improve the phenol glucuronic acid conjugation.
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 showed strong tumor growth inhibition against a KPL-4 breast cancer xenograft model in vivo.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. kawadahto@chugai-pharm.co.jp
authors.forename: Hatsuo
authors.initials: H
authors.lastname: Kawada
authors.forename: Hirosato
authors.initials: H
authors.lastname: Ebiike
authors.forename: Masao
authors.initials: M
authors.lastname: Tsukazaki
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Nakamura
authors.forename: Kenji
authors.initials: K
authors.lastname: Morikami
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yoshinari
authors.forename: Miyuki
authors.initials: M
authors.lastname: Yoshida
authors.forename: Kotaro
authors.initials: K
authors.lastname: Ogawa
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shimma
authors.forename: Takuo
authors.initials: T
authors.lastname: Tsukuda
authors.forename: Jun
authors.initials: J
authors.lastname: Ohwada
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D020723:Glucuronic Acid / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D010636:Phenols / Q000737:chemistry*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D010636:Phenols; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C527741:pyrrolopyrimidine; D020723:Glucuronic Acid