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Optimization of diaryl amine derivatives as kinesin spindle protein inhibitors
Affiliation:1. Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan;2. Graduate School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan;3. Faculty of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-osaka 577-8502, Japan;1. Scientific Technological Center of Organic and Pharmaceutical Chemistry of National Academy of Science of Republic of Armenia, Institute of Fine Organic Chemistry of A.L.Mnjoyan, Ave. Azatutyan 26, Yerevan 0014, Armenia;2. Dipartimento di Chimica G. Ciamician, Alma Mater Studiorum-Università di Bologna, Via F. Selmi 2, Bologna 40126, Italy;3. Aristotle University of Thessaloniki, School of Pharmacy, Thessaloniki 54124, Greece;1. Dipartimento NEUROFARBA, Sezione Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Italy;2. Dipartimento FARMACIA, Università degli Studi di Pisa, Italy;3. Departments of Clinical Neurosciences, Cell Biology & Anatomy, and Biochemistry & Molecular Biology and Hotchkiss Brain Institute, University of Calgary, Calgary, Canada T2N4N1;5. Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea;6. Molecular Genetics Research Laboratory, Graduate School of Science, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan;4. Cell Division and Cancer Group, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain;1. Department of Chemistry & Pharmaceutical Sciences, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy;2. Molecular Simulation Engineering (MOSE) Laboratory, DI3, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy;3. National Interuniversity Consortium for Material Science and Technology (INSTM), Research Unit MOSE-DEA, University of Trieste, Trieste, Italy;4. Department of Pharmaceutical and Medicinal Chemistry, Corrensstrasse 48, 48149 Münster, Germany
Abstract:Structure–activity relationship studies of diaryl amine-type KSP inhibitors were carried out. Diaryl amine derivatives with a pyridine ring or urea group were less active when compared with the parent carboline and carbazole derivatives. Optimization studies of a lactam-fused diphenylamine-type KSP inhibitor revealed that the aniline NH group and 3-CF3 phenyl group were indispensable for potent KSP inhibition. Modification with a seven-membered lactam-fused phenyl group and a 4-(trifluoromethyl)pyridin-2-yl group improved aqueous solubility while maintaining potent KSP inhibitory activity. From these studies, we identified novel diaryl amine-type KSP inhibitors with a favorable balance of potency and solubility.
Keywords:Diaryl amine  Kinesin spindle protein  Aqueous solubility
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