4dmx
From Proteopedia
Cathepsin K inhibitor
Structural highlights
Disease[CATK_HUMAN] Defects in CTSK are the cause of pycnodysostosis (PKND) [MIM:265800]. PKND is an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature.[1] [2] [3] [4] Function[CATK_HUMAN] Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation. Publication Abstract from PubMedDirected 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. Optimisation 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. (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.,Dossetter A, Beeley H, Bowyer J, Cook CR, Crawford JJ, Finlayson JE, Heron NM, Heyes C, Highton AJ, Hudson JA, Jestel A, Kenny PW, Krapp S, Martin S, Macfaul PA, McGuire TM, Morentin-Gutierrez P, Morley AD, Morris JJ, Page KM, Rosenbrier-Ribeiro L, Sawney H, Steinbacher S, Smith C, Vickers M J Med Chem. 2012 Jun 28. PMID:22742641[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Beeley H | Bowyer J | Cook CR | Crawford JJ | Dossetter AG | Finlayson JE | Gutierrez PM | Heron NM | Heyes C | Highton AJ | Hudson JA | Jestel A | Kenny PW | Krapp S | MacFaul PA | Martin S | McGuire TM | Morley AD | Morris JJ | Page KM | Rosenbrier Ribeiro L | Sawney H | Smith C | Steinbacher S | Vickers M
