2. Academic Validation
  3. Benzoxazolinone aryl sulfonamides as potent, selective Nav1.7 inhibitors with in vivo efficacy in a preclinical pain model

Benzoxazolinone aryl sulfonamides as potent, selective Nav1.7 inhibitors with in vivo efficacy in a preclinical pain model

  • Bioorg Med Chem Lett. 2017 Jun 15;27(12):2683-2688. doi: 10.1016/j.bmcl.2017.04.040.
Joseph E Pero 1,  Michael A Rossi 2,  Hannah D G F Lehman 2,  Michael J Kelly 3rd 2,  James J Mulhearn 2,  Scott E Wolkenberg 2,  Matthew J Cato 3,  Michelle K Clements 4,  Christopher J Daley 3,  Tracey Filzen 3,  Eleftheria N Finger 3,  Yun Gregan 3,  Darrell A Henze 4,  Aneta Jovanovska 3,  Rebecca Klein 4,  Richard L Kraus 3,  Yuxing Li 3,  Annie Liang 5,  John M Majercak 3,  Jacqueline Panigel 4,  Mark O Urban 5,  Jixin Wang 4,  Ying-Hong Wang 6,  Andrea K Houghton 3,  Mark E Layton 2
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Merck & Co., Inc., West Point, PA 19486, USA. Electronic address: joseph.e.pero@gsk.com.
  • 2 Department of Medicinal Chemistry, Merck & Co., Inc., West Point, PA 19486, USA.
  • 3 Department of In vitro Pharmacology, Merck & Co., Inc., West Point, PA 19486, USA.
  • 4 Department of Neuroscience, Merck & Co., Inc., West Point, PA 19486, USA.
  • 5 Department of In vivo Pharmacology, Merck & Co., Inc., West Point, PA 19486, USA.
  • 6 Department of Drug Metabolism and Pharmacokinetics, Merck & Co., Inc., West Point, PA 19486, USA.
PMID: 28465103 DOI: 10.1016/j.bmcl.2017.04.040
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.

Keywords

Chronic pain; Na(v)1.7 inhibition; Oral bioavailability; Pharmacological selectivity; Voltage-gated sodium channel.

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