Synthetic studies on novel Syk inhibitors. Part 1: Synthesis and structure-activity relationships of pyrimidine-5-carboxamide derivatives

Spleen tyrosine kinase (Syk) is a non-receptor-type tyrosine kinase which mediates diverse responses, in haematopoietic cells. Therefore, Syk is an attractive therapeutic target, and in a study of Syk inhibitors is potentially new therapeutic agents, we discovered the 4-anilinopyrimidine-5-carboxamides. Enzyme screening indicated that an aminoethylamino moiety at the 2-position of the pyrimidine ring was important for Syk inhibitory activity. and an investigation of the substituents at the 4-position revealed that an anilino moiety substituted at the meta position was preferred. These compounds showed high selectivity for Syk, compared to other kinases, such as ZAP-70, c-Src, and PKC, and exhibited good inhibitory activities against 5HT release from RBL-cells. Among them, compound 9a inhibited the passive cutaneous anaphylaxis reaction in mice. with in ID50 of 13 mg/kg following subcutaneous administration. These results suggest that our Compounds are worthy of further evaluation as new anti-allergic agents. (c) 2005 Elsevier Ltd. All rights reserved.