Lead optimization of cathepsin K inhibitors for the treatment of Osteoarthritis

Anthony T Ginnetti; Daniel V Paone; Kausik K Nanda; Jing Li; Marina Busuek; Scott A Johnson; Jun Lu; Stephen M Soisson; Ronald Robinson; John Fisher; Andrea Webber; Gregg Wesolowski; Bennett Ma; Le Duong; Steven Carroll; Christopher S Burgey; Shawn J Stachel

doi:10.1016/j.bmcl.2022.128927

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. Epub 2022 Aug 6.

Authors

Anthony T Ginnetti¹, Daniel V Paone², Kausik K Nanda², Jing Li³, Marina Busuek², Scott A Johnson⁴, Jun Lu⁴, Stephen M Soisson⁴, Ronald Robinson⁵, John Fisher⁶, Andrea Webber⁷, Gregg Wesolowski⁶, Bennett Ma⁸, Le Duong⁶, Steven Carroll⁵, Christopher S Burgey², Shawn J Stachel²

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.

MeSH terms

Animals
Bone and Bones
Cathepsin K
Cathepsins
Chondrocytes
Cysteine Proteinase Inhibitors / chemistry
Cysteine Proteinase Inhibitors / pharmacology
Cysteine Proteinase Inhibitors / therapeutic use
Dogs
Osteoarthritis* / drug therapy
Osteoclasts

Substances

Cysteine Proteinase Inhibitors
Cathepsins
Cathepsin K