1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles: identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile.
The optimization of a series of 5-phenylacetyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives toward the inhibition of Aurora kinases led to the identification of compound 9d. This is a potent inhibitor of Aurora kinases that also shows low nanomolar potency against additional anticancer kinase targets. Based on its high antiproliferative activity on different cancer cell lines, favorable chemico-physical and pharmacokinetic properties, and high efficacy in in vivo tumor models, compound 9d was ultimately selected for further development.
Fancelli
Daniele
D
Nerviano Medical Sciences S.r.l. viale Pasteur 10, 20014 Nerviano, Milan, Italy.
Moll
Jürgen
J
Varasi
Mario
M
Bravo
Rodrigo
R
Artico
Roberta
R
Berta
Daniela
D
Bindi
Simona
S
Cameron
Alexander
A
Candiani
Ilaria
I
Cappella
Paolo
P
Carpinelli
Patrizia
P
Croci
Walter
W
Forte
Barbara
B
Giorgini
Maria Laura
ML
Klapwijk
Jan
J
Marsiglio
Aurelio
A
Pesenti
Enrico
E
Rocchetti
Maurizio
M
Roletto
Fulvia
F
Severino
Dino
D
Soncini
Chiara
C
Storici
Paola
P
Tonani
Roberto
R
Zugnoni
Paola
P
Vianello
Paola
P
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D008297:Male; D051379:Mice; D008958:Models, Molecular; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D011720:Pyrazoles; D011758:Pyrroles; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases