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.

Keywords: Dihydroimidazopyrimidinone; Imidazopyrimidinone; Metabotropic glutamate receptor 5 (mGlu(5)); Positive allosteric modulator (PAM); Schizophrenia.

Figure 1

Evolution strategy of dihydrothiazolopyridone 1 to other 5,6-bicyclic systems.

Figure 2

Dose-dependent effect and calculated terminal unbound brain of 4a on the reversal of amphetamine-induced hyperlocomotion in rats.

Scheme 1

Reagents and conditions: (a) 1,3-dichloroacetone, AcOH, 110 °C, 16 h, 44%; (b) PhOH, K₂CO₃, ACN, 50 °C, 18 h, 53%; (c) LiOH, H₂O/THF, 50 °C, 4 h, 98%; (d) Pd(OH)₂/C, H₂ atm, Et₃N, AcOEt/MeOH, 50 °C, 45 psi, 16 h, in a Parr reactor, 92%; (e) R¹X, CuI, N,N′-dimethylethylenediamine, K₂CO₃, toluene, 120 °C, 16 h, 22–73%.

Scheme 2

Reagents and conditions: (a) for R¹ = Alkyl: R¹X, BuN₄OH, DMF, rt, 2 h, 57–77% and for R¹ = Aryl or heteroaryl: R¹B(OH)₂, Cu(OAc)₂, TMEDA, MeOH/H₂O, rt, 16 h, 48–65%; (b) 1,3-dichloroacetone, DMF, 150 °C, 30 min, microwave irradiation, 15–75%; (c) R²OH, K₂CO₃, ACN, 90 °C, 18 h, 58–95%; (d) I₂, NaIO₄, H₂SO₄, AcOH/water, 80 °C, 4 h, 84%; (e) MeB(OH)₂, Pd(PPh₃)₄, K₂CO₃, 1,4-dioxane/DMF, 150 °C, 45 min, microwave irradiation, 72%.

Scheme 3

Reagents and conditions: (a) Pd(OH)₂/C, H₂ atm, MeOH, 50 °C, 50 psi, 16 h, in a Parr reactor or Raney-Ni, 80 °C, full hydrogen mode, DMF/MeOH in an H-Cube reactor, 5–78%; (b) NBS, benzoyl peroxide, DCE, rt, 16 h, 35%; (c) MeB(OH)₂, Pd(PPh₃)₄, K₂CO₃, 1,4-dioxane/DMF, 150 °C, 45 min, microwave irradiation, 56%; (d) NCS, DMF, 150 °C, 15–20 min, microwave irradiation, 27–55%.