Inhibition of N-type calcium channels by phenoxyanilide analogues.

A series of N,N-dimethylated phenoxyanilide analogues were synthesised and evaluated for their activity at CaV2.2 and CaV3.2 channels. The SAR study conducted, highlighted that steric and hydrophobic interactions primarily enhanced the affinity for the CaV2.2 channel, while an electron-rich aromatic phenoxy ring (R) favoured CaV3.2 inhibition. Whilst the -CF3 phenoxyanilide compounds exhibited a high potency for the CaV2.2 channel, their low CNS MPO scores and high lipophilicity were indicative of a reduced likelihood of crossing the blood-brain barrier (BBB) and suboptimal physicochemical characteristics. The outcomes of this investigation provided valuable insights into the development of selective calcium channel inhibitors for the treatment of neuropathic pain, while building on previous SAR studies performed within the research group.