- Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode
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A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding Ki and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both Gq-coupled intracellular Ca2+ flux and Gs-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.
- Jurica, Elizabeth A.,Wu, Ximao,Williams, Kristin N.,Hernandez, Andres S.,Nirschl, David S.,Rampulla, Richard A.,Mathur, Arvind,Zhou, Min,Cao, Gary,Xie, Chunshan,Jacob, Biji,Cai, Hong,Wang, Tao,Murphy, Brian J.,Liu, Heng,Xu, Carrie,Kunselman, Lori K.,Hicks, Michael B.,Sun, Qin,Schnur, Dora M.,Sitkoff, Doree F.,Dierks, Elizabeth A.,Apedo, Atsu,Moore, Douglas B.,Foster, Kimberly A.,Cvijic, Mary Ellen,Panemangalore, Reshma,Flynn, Neil A.,Maxwell, Brad D.,Hong, Yang,Tian, Yuan,Wilkes, Jason J.,Zinker, Bradley A.,Whaley, Jean M.,Barrish, Joel C.,Robl, Jeffrey A.,Ewing, William R.,Ellsworth, Bruce A.
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supporting information
p. 1417 - 1431
(2017/03/08)
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- Metal- and ligand-free Ullmann-type C-O and C-N coupling reactions promoted by potassium tert-butoxide
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A simple, metal- and ligand-free procedure for the Ullmann-type C-O coupling reactions has been achieved by allowing aryl bromides to react with a variety of phenols in the presence of t-BuOK. Moderate to excellent yields of O-arylation products are obtained under mild conditions in a short time. In addition, two examples of C-N coupling reactions are also reported. A benzyne mechanism is proposed according to the experiment data.
- Yang, Shuliang,Wu, Cunqi,Ruan, Mingbo,Yang, Yanqin,Zhao, Yongxia,Niu, Jiajia,Yang, Wei,Xu, Jingwei
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supporting information; experimental part
p. 4288 - 4292
(2012/09/22)
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