Journal Article
Discovery of a novel series of indoline carbamate and indolinylpyrimidine derivatives as potent GPR119 agonists
Sato, K; Murata, T; Sugimoto, H; Rikimaru, K; Imoto, H; Kamaura, M; Negoro, N; Tsujihata, Y; Miyashita, H; Odani, T; ,
Bioorganic & Medicinal Chemistry
ISSN: 0968-0896
EISSN: 1464-3391
PERGAMON-ELSEVIER SCIENCE LTD
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. (C) 2014 Elsevier Ltd. All rights reserved.
Conformation; GPCR; GPR119 agonist; Indoline; Type 2 diabetes mellitus; 2 [1 (5 ethylpyrimidin 2 yl)piperidin 4 yl]propyl 7 fluoro 5 (methylsulfonyl) 2,3 dihydro 1h indole 1 carboxylate; 2 [1 (tert butoxycarbonyl)piperidin 4 yl]propyl 5 (methylsulfonyl) 2,3 dihydro 1h indole 1 carboxylate; 4 (2 hydroxyethyl)piperidine derivative; 4 fluoro 2,3 dihydro 1h indole; 4 fluoro 5 (methylsulfanyl) 2,3 dihydro 1h indole; 4 methyl 5 (methylsufonyl) 2,3 dihydro 1h indole; 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; 5 (methylsulfonyl)indoline; 6 fluoro 2,3 dihydro 1h indole; 6 fluoro 5 (methylsufonyl) 2,3 dihydro 1h indole; 6 methoxy 2,3 dihydro 1h indole; antidiabetic agent; benzyl 4 (2 hydroxypropyl)piperidine 1 carboxylate; G protein coupled receptor; G protein coupled receptor 119; G protein coupled receptor 119 agonist; glucose; indoline carbamate derivative; indolinylpyrimidine derivative; insulin; lead; n aryl indoline derivative; pyrrolo[2,3 d]pyrimidine derivative; unclassified drug; antidiabetic agent; G protein coupled receptor; GPR119 protein, rat; indole derivative; indoline; animal experiment; animal model; antidiabetic activity; article; controlled study; drug conformation; drug design; drug identification; drug potency; drug synthesis; glucose blood level; insulin release; male; nonhuman; oral glucose tolerance test; rat; structure activity relation; animal; chemical structure; chemistry; glucose tolerance test; synthesis; Rattus; Animals; Glucose Tolerance Test; Hypoglycemic Agents; Indoles; Molecular Structure; Rats; Receptors, G-Protein-Coupled; Structure-Activity Relationship