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 Ca_V2.2 and Ca_V3.2 channels. The SAR study conducted, highlighted that steric and hydrophobic interactions primarily enhanced the affinity for the Ca_V2.2 channel, while an electron-rich aromatic phenoxy ring (R) favoured Ca_V3.2 inhibition. Whilst the -CF₃ phenoxyanilide compounds exhibited a high potency for the Ca_V2.2 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.