Optimization of Novel Aza-benzimidazolone mGluR2 PAMs with Respect to LLE and PK Properties and Mitigation of CYP TDI

Abstract

Investigation of a novel amino-aza-benzimidazolone structural class of positive allosteric modulators (PAMs) of metabotropic glutamate receptor 2 (mGluR2) identified [2.2.2]-bicyclic amine 12 as an intriguing lead structure due to its promising physicochemical properties and lipophilic ligand efficiency (LLE). Further optimization led to chiral amide 18, which exhibited strong in vitro activity and attractive pharmacokinetic (PK) properties. Hypothesis-driven target design identified compound 21 as a potent, highly selective, orally bioavailable mGluR2 PAM, which addressed a CYP time-dependent inhibition (TDI) liability of 18, while maintaining excellent drug-like properties with robust in vivo activity in a clinically validated model of antipsychotic potential.

Absolute configuration assignment of (+)‐fluralaner using vibrational circular dichroism

“…The VCD chiroptical technique of combining experimental VCD spectra with density functional theory (DFT) calculated spectra has proven to be an accurate way for determining the absolute configuration of chiral molecules . At MRL (Merck Research Laboratories), the absolute configurations of more than 350 diverse compounds have been assigned, most of which remain proprietary, but some of which have supported publications . The diversity in chemical structure has led to an accumulation of experience in dealing with a vast array of chemistry complexities and functionalities when applying VCD.…”

“…[4][5][6][7][8][9][10][11][12] At MRL (Merck Research Laboratories), the absolute configurations of more than 350 diverse compounds have been assigned, most of which remain proprietary, but some of which have supported publications. 5,[13][14][15][16][17][18] The diversity in chemical structure has led to an accumulation of experience in dealing with a vast array of chemistry complexities and functionalities when applying VCD. Commonly, it is possible to identify all functional groups of a given molecule in the VCD spectrum.…”

Determination of the Absolute Configurations of Chiral Drugs Using Chiroptical Spectroscopy

“…Most of the reported chiroptical spectral analyses for chiral drugs were accomplished via visual spectral analyses. A table summarizing the chiral drugs whose ACs were investigated [34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90] using chiroptical spectroscopic methods are summarized in Table 1. Occasional reviews have also highlighted some of these chiral drugs [42,65,91,92].…”

Allosteric modulators in CNS disorders: review

“…Studies show that Group II (mGlu2 and mGlu3) agonists or mGlu2 PAMs are capable of controlling the positive symptoms, while mGlu5 PAMs have efficacy in reducing all symptoms clusters schizophrenia patients. 8 Activation of mGlu4 with positive allosteric modulators is a promising therapeutic area for management of schizophrenia and development of newer antipsychotic medications. The Group III mGlu4-preferring orthosteric agonist LSP1-2111 demonstrated a dose-dependent inhibition of amphetamine-induced hyperactivity and reversal of MK-801 induced deficits in novel object recognition in rats.…”