Aminopiperidine Sulfonamide Ca_v2.2 Channel Inhibitors for the Treatment of Chronic Pain

Abstract

The voltage-gated calcium channel Ca(v)2.2 (N-type calcium channel) is a critical regulator of synaptic transmission and has emerged as an attractive target for the treatment of chronic pain. We report here the discovery of sulfonamide-derived, state-dependent inhibitors of Ca(v)2.2. In particular, 19 is an inhibitor of Ca(v)2.2 that is selective over cardiac ion channels, with a good preclinical PK and biodistribution profile. This compound exhibits dose-dependent efficacy in preclinical models of inflammatory hyperalgesia and neuropathic allodynia and is devoid of ancillary cardiovascular or CNS pharmacology at the doses tested. Importantly, 19 exhibited no efficacy in Ca(v)2.2 gene-deleted mice. The discovery of metabolite 26 confounds further development of members of this aminopiperidine sulfonamide series. This discovery also suggests specific structural liabilities of this class of compounds that must be addressed.

Breaking barriers to novel analgesic drug development

“…Therefore, state-dependent inhibition results in greater inhibition of channels that are repetitively cycling quickly through activated states, potentially conferring at least some selectivity for neurons that are hyperactive. Although several such state-dependent calcium channel inhibitors have demonstrated effective pain relief in several rodent models 185–187 , efficacy in human trials remains to be demonstrated.…”

An approach to identify microRNAs involved in neuropathic pain following a peripheral nerve injury

“…These include the voltage dependent sodium channel SCN9A (Nassar et al, 2004), the sodium channel beta 2 subunit (SCN2B) (Pertin et al, 2005; Lopez-Santiago et al, 2006), the voltage-dependent calcium channels T-type (Choi et al, 2007; Lee et al, 2009; Chen et al, 2010), N-type (Hatakeyama et al, 2001; Kim et al, 2001; Saegusa et al, 2001) and P/Q-type (Luvisetto et al, 2006), the pacemaker channels HCN1 (Momin et al, 2008) and HCN2 (Emery et al, 2011), the ligand-gated, non-selective cation channel TRPV1 (Caterina et al, 2000; Wang et al, 2008) and the transient receptor potential channel TRPM8 (Bautista et al, 2007; Dhaka et al, 2007; Gentry et al, 2010; Knowlton et al, 2010). Some of these targets such as the voltage-dependent calcium channels T-type (Latham et al, 2009; Lee et al, 2014) and N-type (Shao et al, 2012; Adams and Berecki, 2013), and the TRPM8 channel (Knowlton et al, 2011) were originally identified using pharmacological studies. In studies measuring protein expression levels and using pharmacological agents proteins encoded by other of the identified mRNA targets, such as the voltage-dependent sodium channels SCN8A (Deuis et al, 2013), the auxiliary α2δ-1 subunit (Moore et al, 2009, 2011; Bauer et al, 2010) and β (3) subunit (Li et al, 2012) of voltage-gated calcium channels, have also been implicated in the development of either mechanical or cold allodynia.…”

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…For the derivatives with a mixed action on Ca V 2.2 and Ca V 3 channels, the addictive and intoxicating narcotic properties of ethanol were also abrogated (Newton et al, 2008). Other derivatives in this class include pyrazolpiperidines (Subasinghe et al, 2012) and aminopiperidine sulfonamide (Shao et al, 2012), both of which have analgesic properties by virtue of N-type channel blocking action.…”