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J Med Chem. 2012 Oct 25;55(20):8827-37. doi: 10.1021/jm301119s. Epub 2012 Oct 11.

Pharmacokinetic benefits of 3,4-dimethoxy substitution of a phenyl ring and design of isosteres yielding orally available cathepsin K inhibitors.

Author information

1
AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom. crawford.james@gene.com

Abstract

Rational structure-based design has yielded highly potent inhibitors of cathepsin K (Cat K) with excellent physical properties, selectivity profiles, and pharmacokinetics. Compounds with a 3,4-(CH₃O)₂Ph motif, such as 31, were found to have excellent metabolic stability and absorption profiles. Through metabolite identification studies, a reactive metabolite risk was identified with this motif. Subsequent structure-based design of isoteres culminated in the discovery of an optimized and balanced inhibitor (indazole, 38).

PMID:
22984809
DOI:
10.1021/jm301119s
[Indexed for MEDLINE]

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