4DMX

Cathepsin K inhibitor

Summary for 4DMX

• Entry DOI: 10.2210/pdb4dmx/pdb
• Related: 4DMY
• Descriptor: Cathepsin K, (1R,2R)-N-(1-cyanocyclopropyl)-2-{[4-(4-fluorophenyl)piperazin-1-yl]carbonyl}cyclohexanecarboxamide, GLYCEROL, ... (4 entities in total)
• Functional Keywords: cathepsin k inhibitor, osteoarthritis, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Lysosome: P43235
• Total number of polymer chains: 1
• Total formula weight: 24014.05

Authors

Dossetter, A.G.,Beeley, H.,Bowyer, J.,Cook, C.R.,Crawford, J.J.,Finlayson, J.E.,Heron, N.M.,Heyes, C.,Highton, A.J.,Hudson, J.A.,Kenny, P.W.,Martin, S.,MacFaul, P.A.,McGuire, T.M.,Gutierrez, P.M.,Morley, A.D.,Morris, J.J.,Page, K.M.,Rosenbrier Ribeiro, L.,Sawney, H.,Steinbacher, S.,Krapp, S.,Jestel, A.,Smith, C.,Vickers, M. (deposition date: 2012-02-08, release date: 2012-07-11, Last modification date: 2024-10-30)

Primary citation

Dossetter, A.G.,Beeley, H.,Bowyer, J.,Cook, C.R.,Crawford, J.J.,Finlayson, J.E.,Heron, N.M.,Heyes, C.,Highton, A.J.,Hudson, J.A.,Jestel, A.,Kenny, P.W.,Krapp, S.,Martin, S.,MacFaul, P.A.,McGuire, T.M.,Gutierrez, P.M.,Morley, A.D.,Morris, J.J.,Page, K.M.,Ribeiro, L.R.,Sawney, H.,Steinbacher, S.,Smith, C.,Vickers, M.
(1R,2R)-N-(1-cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carbonyl)cyclohexanecarboxamide (AZD4996): a potent and highly selective cathepsin K inhibitor for the treatment of osteoarthritis.
J.Med.Chem., 55:6363-6374, 2012

PubMed Abstract: Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis-based design using existing structural information. Optimization using small substituents, knowledge from matched molecular pairs, and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.

PubMed: 22742641
DOI: 10.1021/jm3007257

Experimental method

X-RAY DIFFRACTION (1.7 Å)