2. Academic Validation
  3. Lead optimization of cathepsin K inhibitors for the treatment of Osteoarthritis

Lead optimization of cathepsin K inhibitors for the treatment of Osteoarthritis

  • Bioorg Med Chem Lett. 2022 Oct 15;74:128927. doi: 10.1016/j.bmcl.2022.128927.
Anthony T Ginnetti 1,  Daniel V Paone 2,  Kausik K Nanda 2,  Jing Li 3,  Marina Busuek 2,  Scott A Johnson 4,  Jun Lu 4,  Stephen M Soisson 4,  Ronald Robinson 5,  John Fisher 6,  Andrea Webber 7,  Gregg Wesolowski 6,  Bennett Ma 8,  Le Duong 6,  Steven Carroll 5,  Christopher S Burgey 2,  Shawn J Stachel 2
Affiliations

Affiliations

  • 1 Discovery Chemistry, MRL, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA. Electronic address: anthony_ginnetti@merck.com.
  • 2 Discovery Chemistry, MRL, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
  • 3 Discovery Process Chemistry, MRL, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
  • 4 Structural Chemistry, MRL, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
  • 5 In Vitro Pharmacology, MRL, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
  • 6 Bone Biology, MRL, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
  • 7 Molecular Biomarkers, MRL, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
  • 8 Pharmacokinetics, Pharmacodynamics & Drug Metabolism, MRL, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
PMID: 35944849 DOI: 10.1016/j.bmcl.2022.128927
Abstract

Cathepsin K (Cat K) is a cysteine protease involved in bone remodeling. In addition to its role in bone biology, Cat K is upregulated in osteoclasts, chondrocytes and synoviocytes in osteoarthritic (OA) disease states making it a potential therapeutic target for disease-modifying OA. Starting from a prior preclinical compound, MK-1256, lead optimization efforts were carried out in the search for potent Cat K inhibitors with improved selectivity profiles with an emphasis on Cathepsin F. Herein, we report the SAR studies which led to the discovery of the highly selective oxazole compound 23, which was subsequently shown to inhibit Cathepsin K in vivo as measured by reduced levels of urinary C-telopeptide of collagen type I in dog.

Keywords

Cathepsin F; Cathepsin K; Free drug hypothesis; Lead Optimization; Osteoarthritis; Protease inhibitor.

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