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Bioorg Med Chem Lett. 2004 Aug 16;14(16):4291-5.

Rational design of potent and selective NH-linked aryl/heteroaryl cathepsin K inhibitors.

Author information

1
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, QC, Canada H9H 3L1. joel_robichaud@merck.com

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).

PMID:
15261289
DOI:
10.1016/j.bmcl.2004.05.087
[Indexed for MEDLINE]

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