Rational design of potent and selective NH-linked aryl/heteroaryl cathepsin K inhibitors.
Prior reports from our laboratories have identified the nonpeptidic inhibitor 2 as a potent and selective Cathepsin K (Cat K) inhibitor. Modelling studies suggested that the introduction of a NH linker between the P3 aryl and P2 leucinamide moieties would allow the formation of a H-bond with the Gly66 residue of Cat K, hopefully increasing potency. Aniline 4 was thus synthesized and showed improved potency over its predecessor 2. Further modelling concluded that a 2-substituted five membered ring could more adequately place the P3 moiety of 4 into the S3 pocket of Cat K. The synthesis of the 2-substituted thiophene 5 confirmed this hypothesis by displaying a slight increase in potency against Cat K (>10-fold increase in potency vs 2) and a good selectivity profile against Cathepsins B, L, and S. This rationally designed inhibitor 5 also displayed increased potency in a functional bone resorption assay (10nM) versus 2 (95 nM).
Robichaud
Joël
J
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, QC, Canada H9H 3L1. joel_robichaud@merck.com
Bayly
Christopher
C
Oballa
Renata
R
Prasit
Peppi
P
Mellon
Christophe
C
Falgueyret
Jean-Pierre
JP
Percival
M David
MD
Wesolowski
Gregg
G
Rodan
Sevgi B
SB
D001665:Binding Sites; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D008958:Models, Molecular
D015853:Cysteine Proteinase Inhibitors; D002403:Cathepsins; D056657:Cathepsin K