1570178-49-2Relevant articles and documents
Discovery of a novel series of indoline carbamate and indolinylpyrimidine derivatives as potent GPR119 agonists
Sato, Kenjiro,Sugimoto, Hiromichi,Rikimaru, Kentaro,Imoto, Hiroshi,Kamaura, Masahiro,Negoro, Nobuyuki,Tsujihata, Yoshiyuki,Miyashita, Hirohisa,Odani, Tomoyuki,Murata, Toshiki
, p. 1649 - 1666 (2014/03/21)
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.
