title: Rational design of potent and selective NH-linked aryl/heteroaryl cathepsin K inhibitors.
abstract: 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).
authors.affiliation: Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, QC, Canada H9H 3L1. joel_robichaud@merck.com
authors.forename: Joël
authors.initials: J
authors.lastname: Robichaud
authors.forename: Christopher
authors.initials: C
authors.lastname: Bayly
authors.forename: Renata
authors.initials: R
authors.lastname: Oballa
authors.forename: Peppi
authors.initials: P
authors.lastname: Prasit
authors.forename: Christophe
authors.initials: C
authors.lastname: Mellon
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Falgueyret
authors.forename: M David
authors.initials: MD
authors.lastname: Percival
authors.forename: Gregg
authors.initials: G
authors.lastname: Wesolowski
authors.forename: Sevgi B
authors.initials: SB
authors.lastname: Rodan
mesh_terms: 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
chemical_list: D015853:Cysteine Proteinase Inhibitors; D002403:Cathepsins; D056657:Cathepsin K