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

Abstract

We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound 4a as a mGlu5 PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation.

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 .…”

“…As an alternative strategy, we turned our attention to other mGlu 5 PAM chemotypes reported by our labs. 23,24 These chemical classes, represented by general structures 2 and 3 , share a structurally-related carbonyl-containing central scaffold, in contrast to the exocyclic amide moiety in 1 . SAR investigation of these series had already revealed aryls as preferred eastern and western substituents for potent mGlu 5 PAM activity and a prominent role of the central core for the modulation of physicochemical properties.…”

Further optimization of the M1 PAM VU0453595: Discovery of novel heterobicyclic core motifs with improved CNS penetration

“…34 The fluorinated heterobiaryl tail moities were readily prepared in two steps as either a benzyl chloride 7 or a benzyl mesylate 8 from commercial benzyl alcohols 6 . Various 5,6- and 6,6-heterobiaryl systems were then alkylated with either 7 or 8 to provide analogs 10 .…”

“…Quinolinone and naphthyridinone analogs 11 of 9 , were made in a single step from 12 , and based on our previous work, cores such as 15 were also accessed in a simple three step procedure. 34 …”

Further optimization of the mGlu5 PAM clinical candidate VU0409551/JNJ-46778212: Progress and challenges towards a back-up compound

“…1) via a fundamentally new molecular mechanism, 3–6 arising from a unique industrial-academic collaboration between Janssen Research and Development and the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD). 7–13 Immediately following its approval as a clinical canidate, we pursued a multidimensional optimization campaign (surveying modifications to the eastern and western aryl moities as well as the central piperidine ring, Figure 1) towards the discovery of a back-up compound within the (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4- c ]pyridine-5(4 H )-yl(aryl)methanone series. 1,2 The optimization plan focused on blocking CYP-mediated aryl oxidation 2 and improving physiochemical properties of the scaffold, all in an effort to identify analogs with increased potency and increased efficacy in an amphetamine-induced hyperlocomotion (AHL) rodent model by a multidimensional optimization campaign (surveying modifications to the eastern and western aryl moities as well as the central piperidine ring) as shown in Figure 1.…”