Spiro-oxindole Piperidines and 3-(Azetidin-3-yl)-1H-benzimidazol-2-ones as mGlu₂ Receptor PAMs

Abstract

Starting from two weak mGlu2 receptor positive allosteric modulator (PAM) HTS hits (4 and 5), a molecular hybridization strategy resulted in the identification of a novel spiro-oxindole piperidine series with improved activity and metabolic stability. Scaffold hopping around the spiro-oxindole core identified the 3-(azetidin-3-yl)-1H-benzimidazol-2-one as bioisoster. Medicinal chemistry optimization of these two novel chemotypes resulted in the identification of potent, selective, orally bioavailable, and brain penetrant mGluR2 PAMs.

Identification of the Candidate mGlu2 Allosteric Modulator THRX-195518 through In Silico Method and Evaluation of Its Neuroprotective Potential against Glutamate-Induced Neurotoxicity in SH-SY5Y Cell Line

“…THRX-195518 is a molecule with a piperidine structure and a molecular weight of 598.73 g/mol (Figure 3). The literature reports that most PAM ligands exhibit a pyrimidine structure [42,43]. When examining drug-likeness and ADMET analysis for THRX-195518 and the other two mGlu2 activators in our study (LY 379268 and JNJ-46281222), it is observed that the molecules exhibit drug-likeness (Table 1).…”

Scaffold Hopping to Imidazo[1,2-a]pyrazin-8-one Positive Allosteric Modulators of Metabotropic Glutamate 2 Receptor

“…These methods are suitable for scaffold hopping because they assess properties important for biological recognition and not just underlying atom connectivity. We have previously developed optimal implementations of these approaches and applied them to identify mGlu2 PAM scaffolds. , Here, our approach was similar and aimed at replacing the central scaffold, the triazolopyridine in 2a , with alternative heterocyclic ring systems. We have databases of prefragmented compounds from internal and commercial sources and use these to search and retrieve alternative 3D-similar heterocycles.…”

“…Within our laboratories, a long-lasting research effort in the mGlu 2 PAM field in collaboration with Addex Therapeutics resulted in the identification of our clinical lead JNJ 40411813 ( 1 , Figure ) from a series of pyridones. , Subsequent backup programs guided by scaffold hopping approaches led to the development of potent and selective imidazopyridine , and triazolopyridine mGlu2 PAMs. , More recently, we again showed how computationally guided scaffold hopping led to the discovery of a spirooxindole series of mGlu2 PAMs …”

“…16,17 More recently, we again showed how computationally guided scaffold hopping led to the discovery of a spirooxindole series of mGlu2 PAMs. 18 To take full advantage of our large data sets and deep SAR understanding, a scaffold hopping exercise was conducted to further identify new chemotypes. Computational approaches using 3D shape and electrostatic similarity helped identify a new scaffold from triazolopyridine 2a (Figure 2).…”