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
  • 1. GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. [email protected]
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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