Optimization of ADME Properties for Sulfonamides Leading to the Discovery of a T‑Type Calcium Channel Blocker, ABT-639

The discovery of a novel peripherally acting and selective Ca_v3.2 T-type calcium channel blocker, ABT-639, is described. HTS hits <b>1</b> and <b>2</b>, which have poor metabolic stability, were optimized to obtain <b>4</b>, which has improved stability and oral bioavailability. Modification of <b>4</b> 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

Synthesis and Pharmacology of (Pyridin-2-yl)methanol Derivatives as Novel and Selective Transient Receptor Potential Vanilloid 3 Antagonists

Transient receptor potential vanilloid 3 (TRPV3) is a Ca²⁺- and Na⁺-permeable channel with a unique expression pattern. TRPV3 is found in both neuronal and non-neuronal tissues, including dorsal root ganglia, spinal cord, and keratinocytes. Recent studies suggest that TRPV3 may play a role in inflammation, pain sensation, and skin disorders. TRPV3 studies have been challenging, in part due to a lack of research tools such as selective antagonists. Herein, we provide the first detailed report on the development of potent and selective TRPV3 antagonists featuring a pyridinyl methanol moiety. Systematic optimization of pharmacological, physicochemical, and ADME properties of original lead <b>5a</b> resulted in identification of a novel and selective TRPV3 antagonist <b>74a</b>, which demonstrated a favorable preclinical profile in two different models of neuropathic pain as well as in a reserpine model of central pain