Discovery and optimization of a novel series of pyrazolyltetrahydropyran N-type calcium channel (Cav 2.2) blockers for the treatment of pain

[Display omitted] •Optimized a novel series of pyrazoles as potent N-type calcium channel blockers.•Compounds 9 and 22 were orally bioavailable in rats.•Compounds 9 and 22 were efficacious in rat complete Freund’s adjuvant model of inflammatory pain.•Compound 9 was efficacious in rat chronic constriction injury model of neuropathic pain. A novel series of pyrazolyltetrahydropyran N-type calcium channel blockers are described. Structural modifications of the series led to potent compounds in both a cell-based fluorescent calcium influx assay and a patch clamp electrophysiology assay. Representative compounds from the series were bioavailable and showed efficacy in the rat CFA and CCI models of inflammatory and neuropathic pain.