Dihydrothiazolopyridone Derivatives as a Novel Family of Positive Allosteric Modulators of the Metabotropic Glutamate 5 (mGlu₅) Receptor

Abstract

Starting from a singleton chromanone high throughput screening (HTS) hit, we describe a focused medicinal chemistry optimization effort leading to the identification of a novel series of phenoxymethyl-dihydrothiazolopyridone derivatives as selective positive allosteric modulators (PAMs) of the metabotropic glutamate 5 (mGlu5) receptor. These dihydrothiazolopyridones potentiate receptor responses in recombinant systems. In vitro and in vivo drug metabolism and pharmacokinetic (DMPK) evaluation allowed us to select compound 16a for its assessment in a preclinical animal screen of possible antipsychotic activity. 16a was able to reverse amphetamine-induced hyperlocomotion in rats in a dose-dependent manner without showing any significant motor impairment or overt neurological side effects at comparable doses. Evolution of our medicinal chemistry program, structure activity, and properties relationships (SAR and SPR) analysis as well as a detailed profile for optimized mGlu5 receptor PAM 16a are described.

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

“…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.…”

“…16 Further pharmacological profiling of 4k in glutamate concentration response curve (CRC) fold-shift (FS) experiments in human mGlu 5 expressing cells confirmed cooperativity at mGlu 5 receptors (7.7) (FS = 11 for 1 ). 16 Additionally, 4k was assessed in a broad ancillary screening panel of distinct GPCRs, ion channels and transporters 23 in which only weak interaction (57% inhibition of binding at 10 µM) with the human platelet activating factor (PAF) was found. Moreover, other relevant in vitro ADMET properties were also favorable, including moderate predicted human hepatic clearance (hCL hep = 8.4 mL min −1 kg −1 ), clean P450 inhibition profile (1A2 2C9, 2D6 and 3A4 IC 50 s ≥ 30 µM), and low plasma protein binding ( f u (h,r): 8.2, 6.8).…”

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.…”

Discovery and SAR of a novel series of metabotropic glutamate receptor 5 positive allosteric modulators with high ligand efficiency

“…12 Recent findings from Merck-Addex and these laboratories have unveiled a target-mediated CNS adverse-effect (AE) liability, driven by excessive PAM cooperativity 18 or allosteric agonism, 19,20 respectively, suggesting that PAMs with lower cooperativity and devoid of allosteric agonism may be preferable for obtaining an improved therapeutic index. More recently, we disclosed phenoxy-based tool compounds derived from a dihydrothiazolopyridone 21 and napthyridinone 22 series; these compounds include PAMs with low to moderate efficacy. Although CNS disposition was excellent, optimized modulators maintained relatively high clearance in rat and dog and were notably less potent relative to picolinamide-based acetylenic PAMs, which readily achieve sub-100 nM in vitro potency.…”

“…Based on our recently disclosed 1,3-azole containing tetrahydrobenzothiazole mGlu 5 PAM scaffold, 21 the alternative 5,6-bicyclic thiazole ketone 20 was prepared to examine the effect on potency and metabolic stability relative to the pyrazole 5,6-bicyclic ring systems. Comparator thiazole 20 displayed only a ~3-fold reduction in potency versus 11 ; however, compound 20 was highly metabolized in vitro based upon predicted hepatic clearance in human and rat (Figure 2).…”