Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing |
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| Authors: | Maria Gabriella Brasca Clara Albanese Rachele Alzani Raffaella Amici Nilla Avanzi Dario Ballinari James Bischoff Daniela Borghi Elena Casale Valter Croci Francesco Fiorentini Antonella Isacchi Ciro Mercurio Marcella Nesi Paolo Orsini Wilma Pastori Enrico Pesenti Paolo Pevarello Patrick Roussel Mario Varasi Marina Ciomei |
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| Institution: | 1. Nerviano Medical Sciences Srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy;2. Congenia S.r.l., Milano, Italy;3. Centro Nacional de Investigaciones Oncologicas (CNIO), Spain;4. Accelera, viale Pasteur 10, 20014 Nerviano (MI), Italy;5. Newron, Milan, Italy;6. Basilea Pharmaceutica Ltd, Switzerland;7. Novartis Pharma AG, Switzerland |
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| Abstract: | We have recently reported CDK inhibitors based on the 6-substituted pyrrolo3,4-c]pyrazole core structure. Improvement of inhibitory potency against multiple CDKs, antiproliferative activity against cancer cell lines and optimization of the physico-chemical properties led to the identification of highly potent compounds. Compound 31 (PHA-793887) showed good efficacy in the human ovarian A2780, colon HCT-116 and pancreatic BX-PC3 carcinoma xenograft models and was well tolerated upon daily treatments by iv administration. It was identified as a drug candidate for clinical evaluation in patients with solid tumors. |
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