The synthesis of differentially-substituted 3,5-bis(arylamino)pyrazoles has not yet been documented. During our investigation, we managed to develop a novel, entirely combinatorial synthesis of 3,5-bis(arylamino)-pyrazoles relying on a simple one-pot two-step operation.

Following the discovery of imidazopyridine 1 as a potent IGF-1R tyrosine kinase inhibitor, the aniline part has been modified with the aim to optimize the properties of this series. The structure-activity relationships against IGF-1R kinase activity as well as inhibition of the hERG ion channel are discussed.

We disclose a novel series of insulin-like growth factor-1 receptor kinase inhibitors based on the 3-(pyrimidin-4-yl)-imidazo[1,2-a]pyridine scaffold. The influence on the inhibitory activity of substitution on the imidazopyridine and at the C5 position of the pyrimidine is discussed. In the course of this optimization, we discovered a potent and selective inhibitor with suitable pharmacokinetics for oral administration.

A new class of 1-acetanilide-4-aminopyrazole-substituted quinazoline Aurora kinase inhibitors has been discovered possessing highly potent cellular activity. Continuous infusion into athymic mice bearing SW620 tumors of the soluble phosphate derivative 2 led to dose-proportional exposure of the des-phosphate compound 8 with a high-unbound fraction. The combination of potent cell activity and high free-drug exposure led to pharmacodynamic changes in the tumor at low doses, indicative of Aurora B-kinase inhibition and a reduction in tumor volume.

The Aurora kinases have been the subject of considerable interest as targets for the development of new anticancer agents. While evidence suggests inhibition of Aurora B kinase gives rise to the more pronounced antiproliferative phenotype, the most clinically advanced agents reported to date typically inhibit both Aurora A and B. We have discovered a series of pyrazoloquinazolines, some of which show greater than 1000-fold selectivity for Aurora B over Aurora A kinase activity, in recombinant enzyme assays. These compounds have been designed for parenteral administration and achieve high levels of solubility by virtue of their ability to be delivered as readily activated phosphate derivatives. The prodrugs are comprehensively converted to the des-phosphate form in vivo, and the active species have advantageous pharmacokinetic properties and safety pharmacology profiles. The compounds display striking in vivo activity, and compound 5 (AZD1152) has been selected for clinical evaluation and is currently in phase 1 clinical trials.

5712 The Aurora proteins are a family of serine-threonine kinases that have been shown to play critical roles in coordinating cell progression through mitosis by controlling chromosome segregation and cytokinesis. The irregular expression of Aurora A and B kinases have been implicated in tumor progression; therefore inhibitors of these proteins may have significant utility in the treatment of cancer. As part of a programme to identify small molecule inhibitors of Aurora kinases for clinical evaluation we have developed a series of thiazole- and pyrazole-substituted quinazolines which are potent and specific Aurora Kinase inhibitors. Both series of compounds share many similarities in terms of structure-activity relationships (SAR) and compounds of both types have shown inhibition of phosphorylation of histone H3 when dosed to rodents via mini-pumps. The structure activity relationships within these novel series will be discussed alongside an overview of the compounds’ physical properties and pharmacokinetics which has allowed the selection of a first clinical candidate drug, AZD1152. The pyrazole acetanilide and quinazoline C-6 and C-7 substituents were found to be critical to obtain high levels of cellular potency and in the optimisation of physicochemical and pharmacokinetic properties. For many of the compounds of interest, it was possible to synthesise phosphate derivbatives which allowed profiling of the leading compounds using mini-pump dosing. In human cancer xenograft models grown in immunocompromised rodents, AZD1152 causes pharmacodynamic changes that result in durable anti-tumor growth inhibition at well-tolerated doses. AZD1152 has the potential for activity in a wide range of human tumors and is currently in Phase I clinical trials.

Errors in the mitotic process are thought to be one of the principal sources of the genetic instability that hallmarks cancer. Unsurprisingly, many of the proteins that regulate mitosis are aberrantly expressed in tumour cells when compared to their normal counterparts. These may represent a good source of targets for the development of novel anti-cancer agents. The Aurora kinases represent one such family of mitotic regulators. In recent years there has been intense interest in both understanding the role of the Aurora kinases in cell cycle regulation and also in developing small molecule inhibitors as potential novel anti-cancer drugs. With several companies now starting to take Aurora kinase inhibitors into clinical development, the time is right to review the medicinal chemistry contribution to developing the field, in particular to review the increasingly broad range of small molecule inhibitors with activity against this kinase family.