title: Discovery of a novel series of indoline carbamate and indolinylpyrimidine derivatives as potent GPR119 agonists.
abstract: GPR119 has emerged as an attractive target for anti-diabetic agents. We identified a structurally novel GPR119 agonist 22c that carries a 5-(methylsulfonyl)indoline motif as an early lead compound. To generate more potent compounds of this series, structural modifications were performed mainly to the central alkylene spacer. Installation of a carbonyl group and a methyl group on this spacer significantly enhanced agonistic activity, resulting in the identification of 2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]propyl 7-fluoro-5-(methylsulfonyl)-2,3-dihydro-1H-indole-1-carboxylate (20). To further expand the chemical series of indoline-based GPR119 agonists, several heterocyclic core systems were introduced as surrogates of the carbamate spacer that mimic the presumed active conformation. This approach successfully produced an indolinylpyrimidine derivative 37, 5-(methylsulfonyl)-1-[6-({1-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}oxy)pyrimidin-4-yl]-2,3-dihydro-1H-indole, which has potent GPR119 agonist activity. In rat oral glucose tolerance tests, these two indoline-based compounds effectively lowered plasma glucose excursion and glucose-dependent insulin secretion after oral administration.
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: kenjirou.satou@takeda.com.
authors: Kenjiro
authors: K
authors: Sato
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Hiromichi
authors: H
authors: Sugimoto
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Kentaro
authors: K
authors: Rikimaru
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Hiroshi
authors: H
authors: Imoto
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Masahiro
authors: M
authors: Kamaura
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Nobuyuki
authors: N
authors: Negoro
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Yoshiyuki
authors: Y
authors: Tsujihata
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Hirohisa
authors: H
authors: Miyashita
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Tomoyuki
authors: T
authors: Odani
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Toshiki
authors: T
authors: Murata
mesh_terms: D000818:Animals; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000737:chemistry*; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: C532423:GPR119 protein, rat; D007004:Hypoglycemic Agents; D007211:Indoles; D043562:Receptors, G-Protein-Coupled; C057812:indoline
keywords: Conformation; GPCR; GPR119 agonist; Indoline; Type 2 diabetes mellitus