An Overview, Advantages and Therapeutic Potential of Nonpeptide Positive Allosteric Modulators of Glucagon‐Like Peptide‐1 Receptor

Abstract

Due to uncomfortable injection regimens of peptidic agonists of glucagon‐like peptide‐1 receptor (GLP‐1R), orally available nonpeptide positive allosteric modulators (PAMs) of GLP‐1Rs are foreseen as the possible future mainstream therapy for type 2 diabetes. Herein, current GLP‐1R PAMs are reviewed. Based on the effectiveness and in silico predicted physicochemical properties, pharmacokinetics, and toxicity, possible candidates for further development as oral drugs were selected. The suggestion is that GLP‐1R PAMs might be used orally alone or in combination with dipeptidyl peptidase‐4 (DPP‐4) inhibitors, which could offer an optimal treatment option next to metformin monotherapy in type 2 diabetes mellitus, or in a wider spectrum of indications. Quercetin acts as a GLP‐1R PAM and DPP‐4 inhibitor, and therefore, might be considered as a pioneering agent with a dual mechanism of action, in terms of GLP‐1R positive allosteric modulation and DPP‐4 inhibition for potentiating GLP‐1 dependent effects.

The Race to Bash NASH: Emerging Targets and Drug Development in a Complex Liver Disease

“…242 While most GLP-1R agonists in development are peptides, several companies have disclosed nonpeptidic, small molecule GLP-1R agonists. 243 Several small molecules are in or approaching the clinic and are being investigated for T2DM. It would be assumed, however, that they will also be evaluated for NASH in the near future.…”

Discovery of an Orally Efficacious Positive Allosteric Modulator of the Glucagon-like Peptide-1 Receptor

“…6 Small-molecule positive allosteric modulators (PAMs) of the GLP-1R could also offer a pharmacological strategy for this proven therapeutic target. 7,8 Allosteric modulators would only enhance receptor signaling when the endogenous ligand is present, thereby providing an opportunity to selectively enhance the normal GLP-1 response during nutrient consumption. Several small molecules have been described that potentiate the actions of GLP-1(7−36) at the GLP-1R; 9−11 however, less information exists on the potentiation of GLP-1(9−36).…”

“…To date, only peptide agonists of the GLP-1R are marketed for the treatment of T2DM, but several small-molecule agonists have entered clinical testing, including TTP273 (presumably OAD2), PF-06882961, PF-07081532, and LY3502970 . Small-molecule positive allosteric modulators (PAMs) of the GLP-1R could also offer a pharmacological strategy for this proven therapeutic target. , Allosteric modulators would only enhance receptor signaling when the endogenous ligand is present, thereby providing an opportunity to selectively enhance the normal GLP-1 response during nutrient consumption. Several small molecules have been described that potentiate the actions of GLP-1(7–36) at the GLP-1R; − however, less information exists on the potentiation of GLP-1(9–36). , We recently reported a cryoEM structure of LSN3160440 in complex with the GLP-1R, full-length GLP-1, and the Gs protein .…”

Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening

“…Interestingly, two PAM agonists of GLP-1R, 6,7-dichloro-3-methanesulfonyl-2-tert-butylamino-quinoxaline (compound 2) and 4-(3-benzyloxyphenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl) pyrimidine (BETP) [6,7,22], have been found to covalently link with C347 6x36b (Wootten numbering in superscript) [23] at the intracellular end of TM6, sharing a similar region as the NAMs (such as NNC0640 and PF-0637222) [7,21]. In the case of GLP-1R, a variety of allosteric modulators have been described [24,25], including compound 19 [26], ZINC19797057 [27], compound 3286 [28], CD3878-F005 [29], HTL26119 [30] and ZINC00702587 [31], thereby greatly enhancing our knowledge about the small molecule allosterism of this important drug target.…”