6-Substituted pyrrolo[3,4-c]pyrazoles: an improved class of CDK2 inhibitors.
We have recently reported a new class of CDK2/cyclin A inhibitors based on a bicyclic tetrahydropyrrolo[3,4-c]pyrazole scaffold. The introduction of small alkyl or cycloalkyl groups in position 6 of this scaffold allowed variation at the other two diversity points. Conventional and polymer-assisted solution phase chemistry provided a way of generating compounds with improved biochemical and cellular activity. Optimization of the physical properties and pharmacokinetic profile led to a compound which exhibited good efficacy in vivo on A2780 human ovarian carcinoma.
Brasca
Maria Gabriella
MG
Oncology Business Unit, Department of Chemistry, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano MI, Italy. gabriella.brasca@nervianoms.com
Albanese
Clara
C
Amici
Raffaella
R
Ballinari
Dario
D
Corti
Luca
L
Croci
Valter
V
Fancelli
Daniele
D
Fiorentini
Francesco
F
Nesi
Marcella
M
Orsini
Paolo
P
Orzi
Fabrizio
F
Pastori
Wilma
W
Perrone
Ettore
E
Pesenti
Enrico
E
Pevarello
Paolo
P
Riccardi-Sirtori
Federico
F
Roletto
Fulvia
F
Roussel
Patrick
P
Varasi
Mario
M
Vulpetti
Anna
A
Mercurio
Ciro
C
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000145:classification / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000145:classification / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000145:classification* / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*
D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D006131:Growth Inhibitors; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011758:Pyrroles; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2