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Synthesis and Structure‐Activity Relationships of N ‐(4‐Benzamidino)‐Oxazolidinones: Potent and Selective Inhibitors of Kallikrein‐Related Peptidase 6
Author(s) -
De Vita Elena,
Smits Niels,
Hurk Helma,
Beck Elizabeth M.,
Hewitt Joanne,
Baillie Gemma,
Russell Emily,
Pannifer Andrew,
Hamon Véronique,
Morrison Angus,
McElroy Stuart P.,
Jones Philip,
Ignatenko Natalia A.,
Gunkel Nikolas,
Miller Aubry K.
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900536
Subject(s) - potency , chemistry , in vivo , in vitro , kallikrein , biochemistry , pharmacology , docking (animal) , carboxamide , enzyme , stereochemistry , biology , medicine , microbiology and biotechnology , nursing
Kallikrein‐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 ((5 R )‐3‐(4‐carbamimidoylphenyl)‐ N ‐(( S )‐1‐(naphthalen‐1‐yl)propyl)‐2‐oxooxazolidine‐5‐carboxamide) and 34 ((5 R )‐3‐(6‐carbamimidoylpyridin‐3‐yl)‐ N ‐((1 S )‐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.