Kinase lead optimization

Experimental screening established that compound 42 shown in Fig. 8.11 disrupts ZipA-FtsZ protein-protein interaction. However, previous studies suggested potential issues with toxicity associated with this class of compounds. Additionally such amine-substituted pyridyl-pyrimidines are heavily patented in the context of kinase inhibition. Both of these factors limit the scope of the subsequent lead optimization process, to transform this compound into a viable drug. Knowledge that compound 42 was a micromolar inhibitor of ZipA-FtsZ was exploited by searching for molecules that were similar in shape. 

Fig. 14.11 Selected examples for lead optimization under consideration of multiple parameters simultaneously (A) thrombin inhibitors, (B) p38 MAP kinase inhibitors, (C) MMP-8 inhibitors.

Lead optimization and structure-based design of deoxycytidine kinase inhibitors with potent in vitro and in vivo activity... 

Rho kinase (ROCK) inhibitors are potential therapeutic agents for cardiovascular diseases ranging from hypertension to atherosclerosis. Our chemistry effort has been focused around the initial lead dihydropyrimidine 1, which suffered from poor oral bioavailability, moderate Rho kinase potency, and potent P450 inhibition. Lead optimization efforts resulted in the identification of 2 which represents an improvement in all three properties. The SAR and X-Ray cocrystal structure of an advanced compound will be described. 

Li B, Cociorva OM, Nomanbhoy T, Weissig H, Li Q, Nakamura K, Liyanage M, Zhang MC, Shih AY, Aban A, Hu Y, Cajica J, Pham L, Kozarich JW, Shreder KR (2013a) Hit-to-lead optimization and kinase selectivity of imidazo[l,2-a]quinoxalin-4-amine derived JNKl inhibitors. Bioorg Med Chem Lett 23(18) 5217-5222. doi 10.1016/j.bmcl.2013.06.087... 

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