Isosteric replacements for benzothiazoles and optimisation to potent Cathepsin K inhibitors free from hERG channel inhibition.
Bioorg Med Chem Lett
; 22(17): 5563-8, 2012 Sep 01.
Article
en En
| MEDLINE
| ID: mdl-22858142
ABSTRACT
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.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Benzotiazoles
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Canales de Potasio Éter-A-Go-Go
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Catepsina K
/
Nitrilos
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2012
Tipo del documento:
Article