ABSTRACT
Studies on human genetics have suggested that inhibitors of the Nav1.7 voltage-gated sodium channel hold considerable promise as therapies for the treatment of chronic pain syndromes. Herein, we report novel, peripherally-restricted benzoxazolinone aryl sulfonamides as potent Nav1.7 inhibitors with excellent selectivity against the Nav1.5 isoform, which is expressed in the heart muscle. Elaboration of initial lead compound 3d afforded exemplar 13, which featured attractive physicochemical properties, outstanding lipophilic ligand efficiency and pharmacological selectivity against Nav1.5 exceeding 1000-fold. Key structure-activity relationships associated with oral bioavailability were leveraged to discover compound 17, which exhibited a comparable potency/selectivity profile as well as full efficacy following oral administration in a preclinical model indicative of antinociceptive behavior.
Subject(s)
Analgesics/pharmacology , Benzoxazoles/pharmacology , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Pain/drug therapy , Sulfonamides/pharmacology , Administration, Oral , Analgesics/administration & dosage , Analgesics/chemistry , Animals , Benzoxazoles/administration & dosage , Benzoxazoles/chemistry , Biological Availability , Disease Models, Animal , Dose-Response Relationship, Drug , Formaldehyde/administration & dosage , Humans , Mice , Molecular Structure , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/metabolism , Pain/chemically induced , Rats , Structure-Activity Relationship , Sulfonamides/administration & dosage , Sulfonamides/chemistryABSTRACT
Elevated plasma homocysteine (Hcy) levels are an independent risk factor for the onset and progression of Alzheimer's disease. Reduction of Hcy to normal levels therefore presents a new approach for disease modification. Hcy is produced by the cytosolic enzyme S-adenosylhomocysteine hydrolase (AHCY), which converts S-adenosylhomocysteine (SAH) to Hcy and adenosine. Herein we describe the design and characterization of novel, substrate-based S-adenosylhomocysteine hydrolase inhibitors with low nanomolar potency in vitro and robust activity in vivo.
