Improved Cav2.2 channel inhibitors through a gem -dimethylsulfone bioisostere replacement of a labile sulfonamide
We report the investigation of sulfonamide-derived Cav2.2 inhibitors to address drug-metabolism liabilities with this lead class of analgesics. Modification of the benzamide substituent provided improvements in both potency and selectivity. However, we discovered that formation of the persistent 3-(trifluoromethyl)benzenesulfonamide metabolite was an endemic problem in the sulfonamide series and that the replacement of the center aminopiperidine scaffold failed to prevent this metabolic pathway. This issue was eventually addressed by application of a bioisostere strategy. The new gem-dimethyl sulfone series retained Cav2.2 potency without the liability of the circulating sulfonamide metabolite.
Shao, Pengcheng P.,Ye, Feng,Chakravarty, Prasun K.,Herrington, James B.,Dai, Ge,Bugianesi, Randal M.,Haedo, Rodolfo J.,Swensen, Andrew M.,Warren, Vivien A.,Smith, McHardy M.,Garcia, Maria L.,McManus, Owen B.,Lyons, Kathryn A.,Li, Xiaohua,Green, Mitchell,Jochnowitz, Nina,McGowan, Erin,Mistry, Shruti,Sun, Shu-Yu,Abbadie, Catherine,Kaczorowski, Gregory J.,Duffy, Joseph L.
Aminopiperidine sulfonamide Cav2.2 channel inhibitors for the treatment of chronic pain
The voltage-gated calcium channel Cav2.2 (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 v2.2. In particular, 19 is an inhibitor of Cav2.2 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 Cav2.2 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.
Shao, Pengcheng P.,Ye, Feng,Chakravarty, Prasun K.,Varughese, Deepu J.,Herrington, James B.,Dai, Ge,Bugianesi, Randal M.,Haedo, Rodolfo J.,Swensen, Andrew M.,Warren, Vivien A.,Smith, McHardy M.,Garcia, Maria L.,McManus, Owen B.,Lyons, Kathryn A.,Li, Xiaohua,Green, Mitchell,Jochnowitz, Nina,McGowan, Erin,Mistry, Shruti,Sun, Shu-Yu,Abbadie, Catherine,Kaczorowski, Gregory J.,Duffy, Joseph L.
p. 9847 - 9855
(2013/01/16)
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