Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing

  • Bioorg Med Chem. 2010 Mar 1;18(5):1844-53. doi: 10.1016/j.bmc.2010.01.042.
Maria Gabriella Brasca  1 ,  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 ,  Daniele Volpi ,  Anna Vulpetti ,  Marina Ciomei
Affiliations
  • 1. Nerviano Medical Sciences Srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy. [email protected]
PMID: 20153204 DOI: 10.1016/j.bmc.2010.01.042
Abstract

We have recently reported CDK inhibitors based on the 6-substituted pyrrolo[3,4-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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