Synthesis and Structure‐Activity Relationships of N‐(4‐Benzamidino)‐Oxazolidinones: Potent and Selective Inhibitors of Kallikrein‐Related Peptidase 6

• DOI: 10.1002/cmdc.201900536
• Publication Date: 2019-11-01T13:39:56Z
• Authors: Elena De Vita; Niels Smits; Helma van den Hurk; Elizabeth M. Beck; Joanne Hewitt; Gemma Baillie; Emily Russell; Andrew Pannifer; Véronique Hamon; Angus Morrison; Stuart P. McElroy; Philip Jones; Natalia A. Ignatenko; Nikolas Gunkel; Aubry K. Miller
• Keywords: EXPRESSION; Medicinal & Biomolecular Chemistry; PATHOGENESIS; 610; Chemistry, Medicinal; MELANOMA; Medicinal; 0305 Organic Chemistry; SERINE-PROTEASE NEUROSIN; Inhibitory Concentration 50; Structure-Activity Relationship; 03 medical and health sciences; Rare Diseases; Cytochrome P-450 Enzyme System; TARGETS; Cell Movement; Drug Discovery; Humans; Pharmacology & Pharmacy; 5 Development of treatments and therapeutic interventions; Oxazolidinones; 0303 health sciences; Science & Technology; Binding Sites; 0304 Medicinal and Biomolecular Chemistry; High-throughput screening; Stereoisomerism; Protease inhibitors; Full Papers; 540; Structure-activity relationship; HCT116 Cells; SUBSTRATE-SPECIFICITY; 3. Good health; ALZHEIMERS-DISEASE; Molecular Docking Simulation; Chemistry; Neuroprotective Agents; 5.1 Pharmaceuticals; ACTIVATION PROFILES; Kallikreins; Medicinal Chemistry; SPINAL-CORD; 1115 Pharmacology and Pharmaceutical Sciences; Life Sciences & Biomedicine; Half-Life

AbstractKallikrein‐related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins. Aberrant expression of KLK6 has been found in different cancers and neurodegenerative diseases, and KLK6 is currently studied as a potential target in these pathologies. We report a novel series of KLK6 inhibitors discovered in a high‐throughput screen within the European Lead Factory program. Structure‐guided design based on docking studies enabled rapid progression of a hit cluster to inhibitors with improved potency, selectivity and pharmacokinetic properties. In particular, inhibitors 32 ((5R)‐3‐(4‐carbamimidoylphenyl)‐N‐((S)‐1‐(naphthalen‐1‐yl)propyl)‐2‐oxooxazolidine‐5‐carboxamide) and 34 ((5R)‐3‐(6‐carbamimidoylpyridin‐3‐yl)‐N‐((1S)‐1‐(naphthalen‐1‐yl)propyl)‐2‐oxooxazolidine‐5‐carboxamide) have single‐digit nanomolar potency against KLK6, with over 25‐fold and 100‐fold selectivities against the closely related enzyme trypsin, respectively. The most potent compound, 32, effectively reduces KLK6‐dependent invasion of HCT116 cells. The high potency in combination with good solubility and low clearance of 32 make it a good chemical probe for KLK6 target validation in vitro and potentially in vivo.