Computer-aided design of negative allosteric modulators of metabotropic glutamate receptor 5 (mGluR5): Comparative molecular field analysis of aryl ether derivatives

Abstract

The metabotropic glutamate receptors (mGlu receptors) have emerged as attractive targets for number of neurological and psychiatric disorders. Recently, mGluR5 negative allosteric modulators (NAMs) have gained considerable attention in pharmacological research. Comparative Molecular Field Analysis (CoMFA) was performed on 73 analogues of aryl ether which were reported as mGluR5 NAMs. The study produced a statistically significant model with high correlation coefficient and good predictive abilities.

Impact of GPCR Structures on Drug Discovery

“…A third example from Sosei Heptares is the discovery of a novel mGlu5 negative allosteric modulator, HTL0014242 (Christopher et al, 2015). Although other agents have been developed targeting this receptor (Figure 1) and multiple agents have previously entered the clinic (Christopher et al, 2019;Selvam et al, 2016), the majority of these compounds have now been terminated, again presumably due to poor pharmaceutical properties or other issues. In this case, HTL0014242 was discovered using FBDD approaches and optimized using X-ray structures of examples from the series bound to the mGlu5 receptor (Christopher et al, 2015).…”