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

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

  • Bioorg Med Chem Lett. 2007 Aug 1;17(15):4363-8. doi: 10.1016/j.bmcl.2007.04.029.
Paul Bamborough 1,  Richard M Angell,  Inder Bhamra,  David Brown,  James Bull,  John A Christopher,  Anthony W J Cooper,  Lynsey H Fazal,  Ilaria Giordano,  Lucy Hind,  Vipulkumar K Patel,  Lisa E Ranshaw,  Martin J Sims,  Philip A Skone,  Kathryn J Smith,  Emma Vickerstaff,  Melanie Washington
Affiliations

Affiliation

  • 1 GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Paul.A.Bamborough@gsk.com
PMID: 17600705 DOI: 10.1016/j.bmcl.2007.04.029
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.

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