- Isosteric replacements for benzothiazoles and optimisation to potent Cathepsin K inhibitors free from hERG channel inhibition
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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.
- Dossetter, Alexander G.,Bowyer, Jonathan,Cook, Calum R.,Crawford, James J.,Finlayson, Jonathan E.,Heron, Nicola M.,Heyes, Christine,Highton, Adrian J.,Hudson, Julian A.,Jestel, Anja,Krapp, Stephan,MacFaul, Philip A.,McGuire, Thomas M.,Morley, Andrew D.,Morris, Jeffrey J.,Page, Ken M.,Ribeiro, Lyn Rosenbrier,Sawney, Helen,Steinbacher, Stefan,Smith, Caroline
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scheme or table
p. 5563 - 5568
(2012/09/22)
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- Substituted 1-propiolylpiperazine compounds, their preparation and use
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Substituted 1-propiolylpiperazine compounds corresponding to formula I in which X denotes N or C—R2, and n is an integer from 0 to 8, a method for producing such substituted 1-propiolylpiperazine compounds, pharmaceutical compositions containing such substituted 1-propiolylpiperazine compounds, and the use of such substituted 1-propiolylpiperazine compounds for modulating mGluR5 receptor activity or for treating or inhibiting pain and various other conditions, especially conditions at least partly mediated by the mGluR5 receptor.
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- [4-(HETEROARYL) PIPERAZIN-1-YL]-(2,5-SUBSTITUTED -PHENYL)METHANONE DERIVATIVES AS GLYCINE TRANSPORTER 1 (GLYT-1) INHIBITORS FOR THE TREATMENT OF NEUROLOGICAL AND NEUROPSYCHIATRIC DISORDERS
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The present invention relates to compounds of the general formula (I) wherein R1 is-OR1’,-SR1’ or is a heterocycloalkyl group; R1’ is lower alkyl, lower alkyl substituted by halogen or is -(CH2)n
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Page/Page column 59-60
(2008/06/13)
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- Aryl sulfonamide and sulfonyl compounds as modulators of PPAR and methods of treating metabolic disorders
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Aryl sulfonamide and sulfonyl compounds as modulators of peroxisome proliferator activated receptors, pharmaceutical compositions comprising the same, and methods of treating disease using the same are disclosed.
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Page/Page column 61
(2010/02/14)
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- 1-substituted-4-(thiazolyl-2-)-piperazines, -piperidines and -tetrahydropyridines useful as anxiolytic, psychogeriatric, antidepressant and antischizophrenic agents
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Thiazoles or pharmaceutically acceptable acid addition salts thereof are useful as anxiolytic, psychogeriatric, antidepressant and antischizophrenic agents.
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