title: 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles: identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile.
abstract: 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.
authors.affiliation: Nerviano Medical Sciences S.r.l. viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Fancelli
authors.forename: Jürgen
authors.initials: J
authors.lastname: Moll
authors.forename: Mario
authors.initials: M
authors.lastname: Varasi
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Bravo
authors.forename: Roberta
authors.initials: R
authors.lastname: Artico
authors.forename: Daniela
authors.initials: D
authors.lastname: Berta
authors.forename: Simona
authors.initials: S
authors.lastname: Bindi
authors.forename: Alexander
authors.initials: A
authors.lastname: Cameron
authors.forename: Ilaria
authors.initials: I
authors.lastname: Candiani
authors.forename: Paolo
authors.initials: P
authors.lastname: Cappella
authors.forename: Patrizia
authors.initials: P
authors.lastname: Carpinelli
authors.forename: Walter
authors.initials: W
authors.lastname: Croci
authors.forename: Barbara
authors.initials: B
authors.lastname: Forte
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Giorgini
authors.forename: Jan
authors.initials: J
authors.lastname: Klapwijk
authors.forename: Aurelio
authors.initials: A
authors.lastname: Marsiglio
authors.forename: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.forename: Maurizio
authors.initials: M
authors.lastname: Rocchetti
authors.forename: Fulvia
authors.initials: F
authors.lastname: Roletto
authors.forename: Dino
authors.initials: D
authors.lastname: Severino
authors.forename: Chiara
authors.initials: C
authors.lastname: Soncini
authors.forename: Paola
authors.initials: P
authors.lastname: Storici
authors.forename: Roberto
authors.initials: R
authors.lastname: Tonani
authors.forename: Paola
authors.initials: P
authors.lastname: Zugnoni
authors.forename: Paola
authors.initials: P
authors.lastname: Vianello
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D011758:Pyrroles; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases