Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of N-([1,2,4]Triazolo[4,3- a]pyridin-3-yl)methane-sulfonamides as Potent and Selective hNaV1.7 Inhibitors for the Treatment of Pain

  • J Med Chem. 2018 Jun 14;61(11):4810-4831. doi: 10.1021/acs.jmedchem.7b01826.
Thilo Focken  1 ,  Sultan Chowdhury  1 ,  Alla Zenova  1 ,  Michael E Grimwood  1 ,  Christine Chabot  2 ,  Tao Sheng  1 ,  Ivan Hemeon  1 ,  Shannon M Decker  1 ,  Michael Wilson  1 ,  Paul Bichler  1 ,  Qi Jia  1 ,  Shaoyi Sun  1 ,  Clint Young  1 ,  Sophia Lin  1 ,  Samuel J Goodchild  1 ,  Noah G Shuart  1 ,  Elaine Chang  1 ,  Zhiwei Xie  1 ,  Bowen Li  1 ,  Kuldip Khakh  1 ,  Girish Bankar  1 ,  Matthew Waldbrook  1 ,  Rainbow Kwan  1 ,  Karen Nelkenbrecher  1 ,  Parisa Karimi Tari  1 ,  Navjot Chahal  1 ,  Luis Sojo  1 ,  C Lee Robinette  1 ,  Andrew D White  3 ,  Chien-An Chen  3 ,  Yi Zhang  3 ,  Jodie Pang  2 ,  Jae H Chang  2 ,  David H Hackos  2 ,  J P Johnson Jr  1 ,  Charles J Cohen  1 ,  Daniel F Ortwine  2 ,  Daniel P Sutherlin  2 ,  Christoph M Dehnhardt  1 ,  Brian S Safina  2
Affiliations
  • 1. Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way , Burnaby , BC V5G 4W8 , Canada.
  • 2. Genentech, Inc. , 1 DNA Way , South San Francisco , California 94080 , United States.
  • 3. Chempartner , Building No. 5, 998 Halei Rd. , Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203 , China.
PMID: 29737846 DOI: 10.1021/acs.jmedchem.7b01826
Abstract

The Sodium Channel NaV1.7 has emerged as a promising target for the treatment of pain based on strong genetic validation of its role in nociception. In recent years, a number of aryl and acyl sulfonamides have been reported as potent inhibitors of NaV1.7, with high selectivity over the cardiac isoform NaV1.5. Herein, we report on the discovery of a novel series of N-([1,2,4]triazolo[4,3- a]pyridin-3-yl)methanesulfonamides as selective NaV1.7 inhibitors. Starting with the crystal structure of an acyl sulfonamide, we rationalized that cyclization to form a fused heterocycle would improve physicochemical properties, in particular lipophilicity. Our design strategy focused on optimization of potency for block of NaV1.7 and human metabolic stability. Lead compounds 10, 13 (GNE-131), and 25 showed excellent potency, good in vitro metabolic stability, and low in vivo clearance in mouse, rat, and dog. Compound 13 also displayed excellent efficacy in a transgenic mouse model of induced pain.

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