title: Synthesis and structure-activity relationship of fused-pyrimidine derivatives as a series of novel GPR119 agonists.
abstract: A series of fused-pyrimidine derivatives have been discovered as potent and orally active GPR119 agonists. A combination of the fused-pyrimidine structure and 4-chloro-2,5-difluorophenyl group provided the 5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide derivative 14a as a highly potent GPR119 agonist. Further optimization of the amino group at the 4-position in the pyrimidine ring led to the identification of 2-{1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-yl}acetamide (16b) as an advanced analog. Compound 16b was found to have extremely potent agonistic activity and improved glucose tolerance at 0.1 mg/kg po in mice. We consider compound 16b and its analogs to have clear utility in exploring the practicality of GPR119 agonists as potential therapeutic agents for the treatment of type 2 diabetes mellitus.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. kenji.negoro@astellas.com
authors.forename: Kenji
authors.initials: K
authors.lastname: Negoro
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yonetoku
authors.forename: Ayako
authors.initials: A
authors.lastname: Moritomo
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hayakawa
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Iikubo
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yoshida
authors.forename: Makoto
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005951:Glucose Tolerance Test; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D001786:Blood Glucose; C519854:GPR119 protein, human; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; C030986:pyrimidine