title: Discovery and biological evaluation of novel 4-amino-2-phenylpyrimidine derivatives as potent and orally active GPR119 agonists.
abstract: Novel 4-amino-2-phenylpyrimidine derivatives were synthesized and evaluated as GPR119 agonists. Optimization of the substituents on the phenyl ring at the 2-position and the amino group at the 4-position led to the identification of 3,4-dihalogenated and 2,4,5-trihalogenated phenyl derivatives showing potent GPR119 agonistic activity. The advanced analog (2R)-3-{[2-(4-chloro-2,5-difluorophenyl)-6-ethylpyrimidin-4-yl]amino}propane-1,2-diol (24g) was found to improve glucose tolerance at 1mg/kg po in mice and to show excellent pharmacokinetic profiles in mice and monkeys. Compound 24g also showed an excellent antidiabetic effect in diabetic kk/Ay mice after one week of single daily treatment. These results demonstrate that novel GPR119 agonist 24g improves glucose tolerance not only by enhancing glucose-dependent insulin secretion but also by preserving pancreatic β-cell function.
authors: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. kenji.negoro@astellas.com
authors: Kenji
authors: K
authors: Negoro
authors: Yasuhiro
authors: Y
authors: Yonetoku
authors: Hana
authors: H
authors: Misawa-Mukai
authors: Wataru
authors: W
authors: Hamaguchi
authors: Tatsuya
authors: T
authors: Maruyama
authors: Shigeru
authors: S
authors: Yoshida
authors: Makoto
authors: M
authors: Takeuchi
authors: Mitsuaki
authors: M
authors: Ohta
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005951:Glucose Tolerance Test; D057809:HEK293 Cells; D000882:Haplorhini; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D065609:Cytochrome P-450 CYP1A2 Inhibitors; C519854:GPR119 protein, human; D007004:Hypoglycemic Agents; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D019388:Cytochrome P-450 CYP1A2