2. Academic Validation
  3. Discovery of selective, orally bioavailable, N-linked arylsulfonamide Nav1.7 inhibitors with pain efficacy in mice

Discovery of selective, orally bioavailable, N-linked arylsulfonamide Nav1.7 inhibitors with pain efficacy in mice

  • Bioorg Med Chem Lett. 2017 May 15;27(10):2087-2093. doi: 10.1016/j.bmcl.2017.03.085.
Anthony J Roecker 1,  Melissa Egbertson 2,  Kristen L G Jones 2,  Robert Gomez 2,  Richard L Kraus 3,  Yuxing Li 3,  Amy Jo Koser 3,  Mark O Urban 3,  Rebecca Klein 4,  Michelle Clements 4,  Jacqueline Panigel 4,  Christopher Daley 3,  Jixin Wang 4,  Eleftheria N Finger 3,  John Majercak 3,  Vincent Santarelli 4,  Irene Gregan 3,  Matthew Cato 3,  Tracey Filzen 3,  Aneta Jovanovska 3,  Ying-Hong Wang 5,  Deping Wang 6,  Leo A Joyce 7,  Edward C Sherer 7,  Xuanjia Peng 8,  Xiu Wang 8,  Haiyan Sun 8,  Paul J Coleman 2,  Andrea K Houghton 3,  Mark E Layton 2
Affiliations

Affiliations

  • 1 Department of Discovery Chemistry Merck & Co., Inc., West Point, PA 19486, USA. Electronic address: [email protected].
  • 2 Department of Discovery Chemistry Merck & Co., Inc., West Point, PA 19486, USA.
  • 3 Department of Pharmacology Merck & Co., Inc., West Point, PA 19486, USA.
  • 4 Department of Neuroscience Merck & Co., Inc., West Point, PA 19486, USA.
  • 5 Department of Drug Metabolism Merck & Co., Inc., West Point, PA 19486, USA.
  • 6 Department of Chemistry Modeling & Informatics Merck & Co., Inc., West Point, PA 19486, USA.
  • 7 Department of Analytical Chemistry Merck & Co., Inc., West Point, PA 19486, USA.
  • 8 WuXi AppTec Co., Ltd, Shanghai, China.
PMID: 28389149 DOI: 10.1016/j.bmcl.2017.03.085
Abstract

The voltage-gated Sodium Channel Nav1.7 is a genetically validated target for the treatment of pain with gain-of-function mutations in man eliciting a variety of painful disorders and loss-of-function mutations affording insensitivity to pain. Unfortunately, drugs thought to garner efficacy via Nav1 inhibition have undesirable side effect profiles due to their lack of selectivity over channel isoforms. Herein we report the discovery of a novel series of orally bioavailable arylsulfonamide Nav1.7 inhibitors with high levels of selectivity over Nav1.5, the Nav isoform responsible for cardiovascular side effects, through judicious use of parallel medicinal chemistry and physicochemical property optimization. This effort produced inhibitors such as compound 5 with excellent potency, selectivity, behavioral efficacy in a rodent pain model, and efficacy in a mouse itch model suggestive of target modulation.

Keywords

Arylsulfonamide; Ion channel; Na(v)1.7; Pain; Selectivity.

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