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The discovery of a novel peripherally acting and selective Cav3.2 T-type calcium channel blocker, ABT-639, is described. HTS hits 1 and 2, which have poor metabolic stability, were optimized to obtain 4, which has improved stability and oral bioavailability. Modification of 4 to further improve ADME properties led to the discovery of ABT-639. Following oral administration, ABT-639 produces robust antinociceptive activity in experimental pain models at doses that do not significantly alter psychomotor or hemodynamic function in the rat.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468402 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.5b00023 | DOI Listing |
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