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Bioorg Med Chem Lett. 2007 Aug 1;17(15):4363-8. Epub 2007 Apr 13.

N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck: indazoles as phenol isosteres with improved pharmacokinetics.

Author information

1
GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Paul.A.Bamborough@gsk.com

Abstract

2,4-Dianilino pyrimidines are well-known inhibitors of tyrosine kinases including lymphocyte specific kinase (Lck). Structure-activity relationships at the 4-position are discussed and rationalised. Examples bearing a 2-methyl-5-hydroxyaniline substituent at the 4-position were especially potent but showed poor oral pharmacokinetics. Replacement of this substituent by 4-amino(5-methyl-1H-indazole) yielded compounds with comparable enzyme potency and improved pharmacokinetic properties.

PMID:
17600705
DOI:
10.1016/j.bmcl.2007.04.029
[Indexed for MEDLINE]

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