Piperazinyl Bicyclic Derivatives as Selective Ligands of the α2δ-1 Subunit of Voltage-Gated Calcium Channels

Abstract

The synthesis and pharmacological activities of a new series of piperazinyl quinazolin-4-(3H)-one derivatives acting toward the α2δ-1 subunit of voltage-gated calcium channels (Ca_vα2δ-1) are reported. Different positions of a micromolar HTS hit were explored, and best activities were obtained for compounds containing a small alkyl group in position 3 of the quinazolin-4-(3H)-one scaffold and a 3-methyl-piperazin-1-yl- or 3,5-dimethyl-piperazin-1-yl-butyl group in position 2. The activity was shown to reside in the R enantiomer of the chain in position 2, and several eutomers reached single digit nanomolar affinities. Final modification of the central scaffold to reduce lipophilicity provided the pyrido[4,3-d]pyrimidin-4(3H)-one 16RR, which showed high selectivity for Ca_vα2δ-1 versus Ca_vα2δ-2, probably linked to its improved analgesic efficacy-safety ratio in mice over pregabalin.

Figure 1

Structures of pregabalin (1) and HTS hit 2 and summary of SAR study leading to 16RR.

Scheme 1

Reagents and conditions: (a) DMF, TEA, HATU, 0 °C to rt, overnight; (b) DCM, TEA, 0 °C to rt, overnight; (c) I₂, HMDS, DCM, 0 °C to rt, overnight; (d) Br₂, AcOH, NaOAc, 50 °C, 3 h; (e) ACN, TEA, KI, 90 °C, overnight.

Scheme 2

Reagents and conditions: (a) H₂SO₄, NaNO₂, 0 °C to rt, 16 h; (b) HATU, TEA, DCM, rt, 16 h; (c) I₂, HMDS, DCM, 50 °C, 16 h; (d) TBAF, THF, 0 °C, 30 min; (e) 2,6-lutidine, Tf₂O, DCM, −78 °C, 2 h; (f) DMF/DCM, −78 °C to rt, 4 h (; (g) MsCl, DIPEA, DCM, −78 °C, 5 min; (h) ACN, 80 °C, 24 h.

Figure 2

(A) Effects of pregabalin (1) and 16RR on mechanical hypersensitivity (allodynia) induced by intraplantar injection of capsaicin (1 μg) to mouse hind paw. The results represent the percentage reduction in capsaicin-induced mechanical hypersensitivity. (B) Effect of 1 and 16RR on motor coordination using the rotarod test. The results represent the latencies to fall-down from the elevated rotating drum. Rotarod latencies were measured at 30, 120, and 180 min after administration of vehicle or compounds 1 and 16RR at 20 mg/kg ip.