N-Alkylpyrido[1',2':1,5]pyrazolo-[4,3-d]pyrimidin-4-amines: A new series of negative allosteric modulators of mGlu1/5 with CNS exposure in rodents

Abstract

Selective negative allosteric modulators (NAMs) of each of the group I metabotropic glutamate receptors (mGlu1 and mGlu5) have been well characterized in the literature and offer potential as therapeutics in several disorders of the central nervous system (CNS). Still, compounds that are potent mGlu1/5 NAMs with selectivity versus the other six members of the mGlu family as well as the balance of properties required for use in vivo are lacking. A medicinal chemistry effort centered on the identification of a lead series with the potential of delivering such compounds is described in this Letter. Specifically, a new class of pyrido[1',2':1,5]pyrazolo[4,3-d]pyrimidin-4-amines was designed as a novel isosteric replacement for 4-aminoquinazolines, and compounds from within this chemotype exhibited dual NAM activity at both group I mGlus. One compound, VU0467558 (29), demonstrated near equipotent activity at both receptors, selectivity versus other mGlus, a favorable ancillary pharmacology profile, and CNS exposure in rodents.

Keywords: Central nervous system (CNS); G-protein coupled receptor (GPCR); Metabotropic glutamate receptor subtype 1 (mGlu(1)); Metabotropic glutamate receptor subtype 5 (mGlu(5)); Negative allosteric modulator (NAM).

Figure 1

Quinazoline and quinazoline-like group I mGlu NAMs

Figure 2

Proposal for development of novel mGlu_1/5 NAMs from a pyrido[1′,2′:1,5]pyrazolo[4,3-d]pyrimidin-4-amine scaffold

Scheme 1

Reagents and conditions: (a) Reagents and conditions: (a) KNO₃, H₂SO₄, 0 °C to r.t., 79%; (b) SnCl₂, con. HCl, dioxane, 65%; (c) For R¹ = H, HCONH₂, microwave, 200 °C, 60 min., 98%; (d) For R¹ = CH₃, CH₃C(OEt)₃, formic acid, microwave, 180 °C, 60 min., 24%; (e) POCl₃, microwave, 140 °C, 20 min., 59% (R¹ = H), 54% (R¹ = CH₃); (f) R²NH₂, DIEA, DMF, microwave, 150 °C, 15 min., 43-84%.

Scheme 2

Reagents and conditions: (a) (i) ClCO₂Et, dioxane 100 °C, 16 h, (ii) KO^tBu, isopropanol, microwave, 160 °C, 15 min., 99%; (b) POCl₃, microwave, 140 °C, 20 min., 84%; (c) trans-4-methylcyclohexylamine, DIEA, DMF, rt, 16h., 76%; (d) R³NH₂, DIEA, DMF, microwave, 150 °C, 10 min., 48-77%.