Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing.
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.
Brasca
Maria Gabriella
MG
Nerviano Medical Sciences Srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy. gabriella.brasca@nervianoms.com
Albanese
Clara
C
Alzani
Rachele
R
Amici
Raffaella
R
Avanzi
Nilla
N
Ballinari
Dario
D
Bischoff
James
J
Borghi
Daniela
D
Casale
Elena
E
Croci
Valter
V
Fiorentini
Francesco
F
Isacchi
Antonella
A
Mercurio
Ciro
C
Nesi
Marcella
M
Orsini
Paolo
P
Pastori
Wilma
W
Pesenti
Enrico
E
Pevarello
Paolo
P
Roussel
Patrick
P
Varasi
Mario
M
Volpi
Daniele
D
Vulpetti
Anna
A
Ciomei
Marina
M
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C549971:N-(6,6-dimethyl-5-((1-methylpiperidin-4-yl)carbonyl)-1,4,5,6-tetrahydropyrrolo(3,4-c)pyrazol-3-yl)-3-methylbutanamide; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011758:Pyrroles; D018844:Cyclin-Dependent Kinases