Small Molecule Drug Discovery at the Glucagon-Like Peptide-1 Receptor

Abstract

The therapeutic success of peptide glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus has inspired discovery efforts aimed at developing orally available small molecule GLP-1 receptor agonists. Although the GLP-1 receptor is a member of the structurally complex class B1 family of GPCRs, in recent years, a diverse array of orthosteric and allosteric nonpeptide ligands has been reported. These compounds include antagonists, agonists, and positive allosteric modulators with intrinsic efficacy. In this paper, a comprehensive review of currently disclosed small molecule GLP-1 receptor ligands is presented. In addition, examples of “ligand bias” and “probe dependency” for the GLP-1 receptor are discussed; these emerging concepts may influence further optimization of known molecules or persuade designs of expanded screening strategies to identify novel chemical starting points for GLP-1 receptor drug discovery.

Demonstration of the Innate Electrophilicity of 4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP), a Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor

“…Our studies also revealed that BETP was unstable in BSA and plasma from rat, mouse, and human, which is contrary to a previous speculation that BETP is stable in plasma (Willard et al, 2012a). Similar to the experience with BSA/plasma, incubations of BETP in rat, mouse, and human liver microsomes in the absence of NADPH led to a steady decline in BETP concentrations.…”

“…To a large degree, this difficulty has been attributed to the biochemical mechanisms of class B G-protein-coupled receptors, which require large receptorligand binding sites to induce signaling. Despite this dilemma, a diverse array of low-molecular-weight nonpeptidic ligands have been recently reported as antagonists, agonists, and positive allosteric modulators of GLP-1R with intrinsic efficacy (Knudsen et al, 2007;Teng et al, 2007;Sloop et al, 2010;Willard et al, 2012a). 4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (compound B or BETP) (Fig.…”

Use of Cysteine Trapping to Map Spatial Approximations between Residues Contributing to the Helix N-capping Motif of Secretin and Distinct Residues within Each of the Extracellular Loops of Its Receptor

“…Intracellular cAMP response small molecule GLP-1 receptor agonists) may have such diverse structures (38). A better understanding of the docking of the amino terminus of a natural peptide ligand for the secretin receptor should help provide more insight into the molecular basis for activating a prototypic receptor in this family.…”

Potential of pharmacological modulation of level and activity incretins on diabetes mellitus type 2

“…Учитывая данную проблему, ведётся направленный поиск непептидных молекул, Спасов, Чепляева которые связываются и стимулируют ГПП-1 рецептор. Низкомолекулярные агонисты ГПП-1 рецептора представлены следующими классами соединений: производные хиноксолина, тиофена, пиримидина, циклобутана, фенилаланина, азоантрацена, пиразола, имидазопиридина [30].…”

“…В экспериментальных исследования соединение значительно потенцировало глюкозозависимую секрецию инсулина в островках Лангерганса мышей дикого типа [31]. В библиотеке, насчитывающей 48168 соединений, были найдены вещества S4P и Boc 5, производные циклобутана, которые оказывают эффекты, подобные аналогам ГПП-1 [30,32]. Boc 5 является полным, а S4P частичным агонистами рецептора ГПП-1.…”