title: The design, preparation and SAR of novel small molecule sodium (Na(+)) channel blockers.
abstract: A parallel strategy incorporating predictive modeling of both sodium site 2 blocking activity and cytochrome p450 CYP2D6 enzyme activity as well as experimental data from ADME profiling (eADME) has been applied to the design of new small molecule sodium channel blockers. New structural motifs were identified, which combined sodium channel activity with decreased ADME liabilities. Compounds 10h (site 2, IC(50) =531 nM) and 7j (site 2, IC(50) =149 nM) were identified from two structural classes as sodium channel blockers with favorable in vitro eADME profiles.
authors.affiliation: ArQule Inc, 19 Presidential Way, Woburn, MA 01801, USA. mashwell@rqule.com
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ashwell
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lapierre
authors.forename: Alan
authors.initials: A
authors.lastname: Kaplan
authors.forename: Jenny
authors.initials: J
authors.lastname: Li
authors.forename: Christopher
authors.initials: C
authors.lastname: Marr
authors.forename: Jin
authors.initials: J
authors.lastname: Yuan
mesh_terms: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D015195:Drug Design; D015394:Molecular Structure; D026941:Sodium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D026941:Sodium Channel Blockers; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A