Discovery, optimization, and validation efforts towards positive allosteric modulators of the Glucagon-like peptide 1 receptor and discovery of a novel series of Glucagon-like peptide 1 receptor noncompetitive antagonists. Progress toward the total synthesis of Melearoride A

Abstract

Progress toward the first total synthesis of Melearoride A, a macrolide natural product from the marine fungus Penicillium meleagrinum var. viridiflavum. This compound has shown interesting synergistic antifungal activity against azole-resistant C. albicans in combination with fluconazole. Herein is reported progress in the synthesis and an anticipated route to its completion.

Glucagon-like peptide 1 (GLP-1) and its G-protein coupled receptor, GLP-1R, are implicated in the treatment of type-2 diabetes (T2D). GLP-1 is a gut hormone which functions post-prandially to decrease blood glucose levels by stimulating insulin secretion. GLP-1 has a half-life of 1-4 minutes in the body, and as such does not make for a good therapeutic. GLP-1 mimetics avoid this issue, but they often cause side effects to the point of patient non-compliance. GPCRs are heavily investigated as drug targets and are known to possess allosteric sites in addition to orthosteric sites. Allosteric sites allow for “tuning” of the receptor’s activity up (positive allosteric modulation) or down (negative allosteric modulation). PAMs of GLP-1R may be useful for treatment of T2D, but have remained elusive. Recent efforts have led to the discovery and optimization of the first highly selective and CNS penetrant GLP-1R positive allosteric modulator (PAM), which has shown to modulate the effects of GLP-1 as well as two GLP-1 mimetics, to augment insulin secretion in primary mouse pancreatic islets, and efficacy in potentiating endogenous GLP-1R to reverse haloperidol-induced catalepsy, an in vivo model for Parkinson’s disease. Further investigations into this molecule have presented conflicting results and studies determining the compound’s validity as a GLP-1R PAM are still ongoing.

While primary interest in the Glucagon-like peptide-1 receptor (GLP-1R) within the pharmaceutical industry is directed toward activation and the treatment of T2D, other indications are being investigated which antagonizing the receptor Disease states involving overactive insulin secretion, such as congenital hyperinsulinemia in children, may benefit from antagonism of GLP-1R; however, proof-of-concept studies are difficult due to the lack of tool molecules. A duplexed, functional multi-addition high throughput screen and subsequent optimization effort identified the first orally bioavailable and CNS penetrant GLP-1R noncompetitive antagonist. Antagonist VU0650991 not only blocked exendin-4-stimulated insulin release in islets but also lowered insulin levels while increasing blood glucose in vivo.