1,4,5,6-tetrahydropyrrolo[3,4-c] pyrazoles:: Identification of a potent aurora kinase inhibitor with a favorable antitumor kinase inhibition profile

被引：180

作者：

Fancelli, Daniele ^{[1
]}

Moll, Jurgen ^{[1
]}

Varasi, Mario ^{[1
]}

Bravo, Rodrigo ^{[1
]}

Artico, Roberta ^{[1
]}

Berta, Daniela ^{[1
]}

Bindi, Simona ^{[1
]}

Cameron, Alexander ^{[1
]}

Candiani, Ilaria ^{[1
]}

Cappella, Paolo ^{[1
]}

Carpinelli, Patrizia ^{[1
]}

Croci, Walter ^{[1
]}

Forte, Barbara ^{[1
]}

Giorgini, Maria Laura ^{[1
]}

Klapwijk, Jan ^{[1
]}

Marsiglio, Aurelio ^{[1
]}

Pesenti, Enrico ^{[1
]}

Rocchetti, Maurizio ^{[1
]}

Roletto, Fulvia ^{[1
]}

Severino, Dino ^{[1
]}

Soncini, Chiara ^{[1
]}

Storici, Paola ^{[1
]}

Tonani, Roberto ^{[1
]}

Zugnoni, Paola ^{[1
]}

Vianello, Paola ^{[1
]}

机构：

[1] Nerviano Med Sci SrL, I-20014 Milan, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 24期

关键词：

D O I：

10.1021/jm060897w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：7247 / 7251

页数：5

共 20 条

[1] Bar-Shira A, 2002, CANCER RES, V62, P6803
[2] A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers
Bischoff, JR
Anderson, L
Zhu, YF
Mossie, K
Ng, L
Souza, B
Schryver, B
Flanagan, P
Clairvoyant, F
Ginther, C
Chan, CSM
Novotny, M
Slamon, DJ
Plowman, GD
[J]. EMBO JOURNAL, 1998, 17 (11) : 3052 - 3065
[3] Mitotic phosphorylation of histone H3: Spatio-temporal regulation by mammalian aurora kinases
Crosio, C
Fimia, GM
Loury, R
Kimura, M
Okano, Y
Zhou, HY
Sen, S
Allis, CD
Sassone-Corsi, P
[J]. MOLECULAR AND CELLULAR BIOLOGY, 2002, 22 (03) : 874 - 885
[4] Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores
Ditchfield, C
Johnson, VL
Tighe, A
Ellston, R
Haworth, C
Johnson, T
Mortlock, A
Keen, N
Taylor, SS
[J]. JOURNAL OF CELL BIOLOGY, 2003, 161 (02) : 267 - 280
[5] Potent and selective aurora inhibitors identified by the expansion of a novel scaffold for protein kinase inhibition
Fancelli, D
Berta, D
Bindi, S
Cameron, A
Cappella, P
Carpinelli, P
Catana, C
Forte, B
Giordano, P
Giorgini, ML
Mantegani, S
Marsiglio, A
Meroni, M
Moll, J
Pittalà, V
Roletto, F
Severino, D
Soncini, C
Storici, P
Tonani, R
Varasi, M
Vulpetti, A
Vianello, P
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (08) : 3080 - 3084
[6] George DJ, 1998, PROSTATE, V36, P172, DOI 10.1002/(SICI)1097-0045(19980801)36:3<172::AID-PROS5>3.0.CO
[7] 2-J
[8] GRECO A, 1995, MOL CELL BIOL, V15, P6118
[9] VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo
Harrington, EA
Bebbington, D
Moore, J
Rasmussen, RK
Ajose-Adeogun, AO
Nakayama, T
Graham, JA
Demur, C
Hercend, T
Diu-Hercend, A
Su, M
Golec, JMC
Miller, KM
[J]. NATURE MEDICINE, 2004, 10 (03) : 262 - 267
[10] Jones Robin L, 2005, Expert Opin Drug Saf, V4, P183, DOI 10.1517/14740338.4.2.183

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