Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode

Abstract

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-CF to the pyrrolidine improves the human GPR40 binding K 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 G-coupled intracellular Ca flux and G-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.

Efficient chemoenzymatic synthesis of (2S,3R)-3-hydroxy-3-methylproline, a key fragment in polyoxypeptin A and FR225659

“…Compound 4 was further characterized as its N-Boc counterpart. 19 Spectroscopic data are in agreement with the structure and the 1 H NMR data and 13 C NMR data are consistent with previously reported values. 20…”

Trimethoxyphenyl (TMP) as a Useful Auxiliary for in situ Formation and Reaction of Aryl(TMP)iodonium Salts: Synthesis of Diaryl Ethers

“…[14] Indeed, several examples of S N Ar on 2chloro-5-iodopyridine with O-nucleophiles show a high preference for substitution of the 2-chloro over the 5-iodo moiety. [15] Diaryl ethers containing a pyridyl group have been investigated for their antibacterial activity, [16] and copper-mediated coupling was used to form the diaryl ether CÀ O bond (Scheme 4). In the Scheme 2.…”

FFA4/GPR120: Pharmacology and Therapeutic Opportunities

“…Given the clinical validation of targeting FFA1, there remains significant interest in the potential of novel ligands at this receptor for the treatment of T2DM 14 , 15 , 16 . Recent publications from various pharmaceutical companies several, of what appear, at least in animal models, to be highly effective and potent FFA1 ligands 17 , 18 , 19 , support this. Clearly, issues akin to those that resulted in the removal of fasiglifam from clinical development, including inhibition of BSEP, would need to be addressed directly before further clinical studies commence.…”