| Summary: | The objective of this thesis was to use parallel synthesis to build small molecule libraries of novel compounds with potential as isoform selective type II rho-kinase (ROCK1/2) inhibitors. Considerable effort is ongoing to identify isoform selective ROCK inhibitors, as hyperactivity of the ROCK is implicated in cardiovascular diseases, cancer, diabetes and many other diseases that affect millions of Canadians, and billions of people worldwide. In the absence the extensive structural details of the type II kinase inhibitor binding mode, we have used an empirical approach to the design of type II ROCK inhibitors, based on the conception that such molecules correspond to elongated structures with H-bonding functional elements in their central portion, a motif at one end that mimics the adenine ring in ATP, and a hydrophobic moiety at the other end of the molecule that will interact with an allosteric pocket in the ATP binding region of the kinase. Based on these very general structural requirements, eleven different representative libraries of novel compounds (not described in CAS) were designed and synthesized. In the initial series of compounds, a 2-pyridinone motif was employed as the hinge binding element, and the central portion corresponded to carboxamide substituted oxazoline, oxadiazole, or 2-aminothiazole system, joined through the amide bond to a set of structurally diverse aromatic, heteroaromatic and benzylamine subunits, corresponding to the diversity elements. The preliminary assay results demonstrated that, overall, these compounds were weak and non-selective ROCK1/2 inhibitors when compared to H-1152 as a positive control at 10 μM concentration. However, further structural modification revealed the interest in using an indazole motif as the hinge binder in conjunction with the 2-aminothiazole carboxamide linker. Indeed, more potent activities were observed in the single point assay for a significant portion of the libraries of molecules built around these structural components. Further evaluation of 18 active compounds in a 10-point assay, by Invitrogen, to determine IC50’s revealed that indazole-based inhibitors are active at low micromolar concentrations (1-10 µM), but do not display any significant isoform selectivity. === Pharmaceutical Sciences, Faculty of === Graduate
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