Scaffold Hopping Affords a Highly Selective in vitro and in vivo T-Type Calcium Inhibitor Probe Free From IP Issues

Excerpt

A scaffold hopping approach afforded ML218 (CID 45115620) a selective T-Type Ca²⁺ (Ca_v3.1, Ca_v3.2, Ca_v3.3) inhibitor (Ca_v3.2, IC₅₀ = 150 nM in Ca²⁺ flux; Ca_v3.2 IC₅₀ = 310 nM and Ca_v3.3 IC₅₀ = 270 nM in patch clamp electrophysiology) suitable for in vitro and in vivo studies. ML218 possess excellent dystrophia myotonica protein kinase (DMPK) properties, acceptable in vivo rat PK, excellent brain levels and was efficacious upon oral dosing in a preclinical Parkinsonian model. Thus, ML218 is a powerful new probe to study T-Type Ca²⁺ function in vitro and in vivo.