Isosteric replacements for benzothiazoles and optimisation to potent Cathepsin K inhibitors free from hERG channel inhibition

Autor:	Jonathan Bowyer, Anja Jestel, Adrian John Highton, Philip A. MacFaul, Stephan Krapp, Alexander G. Dossetter, Thomas M. McGuire, Helen Sawney, Jonathan E. Finlayson, Morris Jeffrey James, Stefan Steinbacher, Caroline Smith, Christine Heyes, Andrew David Morley, Calum Cook, Nicola Murdoch Heron, Julian A. Hudson, James J. Crawford, Lyn Rosenbrier Ribeiro, Ken Page
Rok vydání:	2012
Předmět:	Models Molecular Nitrile Stereochemistry Clinical Biochemistry hERG Cathepsin K Pharmaceutical Science Biochemistry chemistry.chemical_compound Structure-Activity Relationship Dogs In vivo Drug Discovery Nitriles Animals Humans Benzothiazoles Molecular Biology Ion channel biology Organic Chemistry Ether-A-Go-Go Potassium Channels Bioavailability Rats Benzothiazole chemistry biology.protein Microsomes Liver Molecular Medicine Matched molecular pair analysis
Zdroj:	Bioorganicmedicinal chemistry letters. 22(17)
ISSN:	1464-3405
Popis:	The discovery of nitrile compound 4, a potent inhibitor of Cathepsin K (Cat K) with good bioavailability in dog is described. The compound was used to demonstrate target engagement and inhibition of Cat K in an in vivo dog PD model. The margin to hERG ion channel inhibition was deemed too low for a clinical candidate and an optimisation program to find isosteres or substitutions on benzothiazole group led to the discovery of 20, 24 and 27; all three free from hERG inhibition.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0e0f37a66cacb75592dfb15ed0b0c6dd https://pubmed.ncbi.nlm.nih.gov/22858142 Zobrazit plný text záznamu Full Text from ScienceDirect