Bioorganic & Medicinal Chemistry Letters 15 (2005) 1315–1319
Benzodipyrazoles: a new class of potent CDK2 inhibitors
Roberto DÕAlessio,a,* Alberto Bargiotti,a Suzanne Metz,c M. Gabriella Brasca,a
Alexander Cameron,a Antonella Ermoli,a Aurelio Marsiglio,b Paolo Polucci,a
Fulvia Roletto,b Marcellino Tibolla,a Michael L. Vazquez,c
Anna Vulpettia and Paolo Pevarelloa
aChemistry Department, Nerviano Medical Sciences, Oncology Business Unit, Viale Pasteur 10, 20014 Nerviano (MI), Italy
bBiology Department, Nerviano Medical Sciences, Oncology Business Unit, Viale Pasteur 10, 20014 Nerviano (MI), Italy
cChemistry Department, Pfizer Inc., St. Louis, MI, USA
Received 21 October 2004; revised 10 January 2005; accepted 12 January 2005
Abstract—The synthesis and the preliminary expansion of this new class of CDK2 inhibitors are presented. The synthesis was
accomplished using a solution-phase protocol amenable to rapid parallel expansion and suitable to be scaled-up in view of possible
lead development. Following a medicinal chemistry program aimed at improving cell permeability and selectivity, a series of com-
pounds with nanomolar activity in the biochemical assay and able to efficiently inhibit tumor cell proliferation has been obtained.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Recent discoveries in diverse fields of biomedical re-
search have elucidated the molecular basis of cell cycle
control and have shown how alterations to this homeo-
static mechanism play an important role in cancer devel-
opment.1,2 Cyclin-dependent kinase
2 (CDK2) in
complex with cyclins E and/or A is a key cell cycle reg-
ulator and continues to be an attractive target for the
discovery of new anti-tumor agents.3 In particular,
inhibitors of CDK2/cyclin A/E have already progressed
into clinical trials with encouraging early results.4,5 Ben-
zodipyrazoles (BDPs) as CDK2 inhibitors originated
from high throughput screening of our internal chemical
collection. The hit compound of this class (1, Fig. 1), a
tetrahydro-benzodipyrazole (TH-BDP) derivative bear-
ing a sulfamidophenyl moiety was found to possess a
remarkable activity on the CDK2/cyclinA complex
(IC50 = 7 nM) and to be an ATP competitive inhibitor.
Figure 1. The structure of 1 and the general formula of BDPs.
the key features for binding of the ligand to the adenine,
phosphate and ribose regions of the ATP pocket,
respectively.
In spite of the notable potency in the biochemical assay,
the anti-proliferative activity of this compound, mea-
sured as inhibition of the A2780 ovarian tumor cell line,
was disappointing (IC50 > 20lM). This is likely due to
the presence of both the sulfamoyl and carbamoyl moi-
eties which, although important for binding, may pre-
vent this compound from penetrating cells efficiently.
A medicinal chemistry program was therefore started
with the aim to improve cell permeability, while main-
taining activity on CDK2/cyclin A/E in the nanomolar
range.
The crystal structure of CDK2/cyclin A in complex with
the compound 1 was determined (Fig. 2). The pyrazole
ring A, the carboxamido and the sulfamido groups are
Keywords: CDK2; Cyclins; Kinase selectivity; Tumor cell proliferation
inhibition.
*
Corresponding author. Tel.: +39 0331 58 1523; fax: +39 0331 58
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.01.023