Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu₅)

Abstract

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlu5 PAMs containing an alkoxy-based linkage as an acetylene replacement. Exploration of several structural features including western pyridine ring isomers, positional amides, linker connectivity/position, and combinations thereof, reveal that these bicyclic modulators generally exhibit steep SAR and within specific subseries display a propensity for pharmacological mode switching at mGlu5 as well as antagonist activity at mGlu3. Structure–activity relationships within a dihydronaphthyridinone subseries uncovered 12c (VU0405372), a selective mGlu5 PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis.

Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia

“…14−20 We then evaluated a diverse array of heterobicyclic scaffolds utilizing optimal Eastern and Western moieties, providing novel mGlu 5 PAM chemotypes, minimally represented by 14−16, which afforded improved DMPK profiles. 14−20 Further optimization efforts incorporated a phenoxy linker 19 as well as exocyclic amide moieties in the 5,6-heterobiaryl scaffolds, which provided series 17.…”

Preliminary investigation of 6,7-dihydropyrazolo[1,5- a ]pyrazin-4-one derivatives as a novel series of mGlu 5 receptor positive allosteric modulators with efficacy in preclinical models of schizophrenia

“…Finally, the replacement of pyridine by pyrimidine resulted in a ~6-fold decrease in the mGlu 5 activity ( 4n vs 4k ). Selectivity screen of selected examples versus the other mGlu family members (mGlu 1–4,6–8 ) 25 revealed, similarly to imidazopyrimidinones 3 24 and a closely related tetranaphthridinone series, 18 potent mGlu 3 antagonist activity for the phenyl-containing congeners (e.g., 4c,f mGlu 3 EC 50 = 74 and 150 nM, respectively, full antagonism). Gratifyingly, the replacement by pyridine decreased the mGlu 3 antagonism ( 4k,l mGlu 3 EC 50 = 6760 and >10,000 nM, respectively) resulting in >50 fold functional selectivity for mGlu 5 for 4k and 4l .…”

“…1–3 In this context, positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 5 (mGlu 5 ) hold high promise by virtue of the close physical and functional relationship between mGlu 5 and NMDA receptors in relevant brain areas. 4–8 Despite the recent association of excessive mGlu 5 receptor activation with target-related liabilities (neuronal necrosis 9 and seizure induction 10 ), the observation that in vivo efficacy in several schizophrenia models has been confirmed for multiple mGlu 5 PAMs, 11–16 combined with the identification of potential alternatives (reduced cooperativity with glutamate, 17,18 signal bias 16 or reduced residence-time and duration of target engagement 19 ) to mitigate these burdens, suggests that further investigations on this novel mechanism are warranted. Resulting from our pioneering industrial-academic collaboration (Janssen Research and Development and the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD)) 20 we have recently reported on the identification 21 and preclinical characterization 16 of the mGlu 5 PAM advanced lead 1 (VU0409551/JNJ-46778212).…”

Discovery and SAR of novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5)

“…13 Among them, we have recently described the discovery of phenoxy-containing mGlu 5 PAMs derived from dihydrothiazolopyridone 14 and naphthyridinone 15 bicyclic cores. As a progression of this work, and in order to further optimize the in vitro and in vivo potencies of dihydrothiazolopyridone 1 , we envisioned the replacement of the thiazolyl ring system by other aromatic five-membered rings (Fig.…”