Bioorganic & Medicinal Chemistry Letters 16 (2006) 915–919
Design, synthesis, and evaluation of 2-alkoxydihydrocinnamates
as PPAR agonists
Ying Lu, Zongru Guo,* Yanshen Guo, Jun Feng and Fengming Chu
Department of Synthetic Medicinal Chemistry, Institute of Materia Medica, Chinese Academy of Medical
Sciences and Peking Union Medical College, Beijing 100050, PR China
Received 6 July 2005; revised 19 October 2005; accepted 31 October 2005
Available online 21 November 2005
Abstract—A series of 2-alkoxydihydrocinnamates were synthesized as PPARc and PPARa dual agonists. In vitro studies in cell
model showed that these compounds were efficacious. Compound 1g was found to be a potent PPARa/c dual agonist and will
be further evaluated for the treatment of type II diabetes.
Ó 2006 Published by Elsevier Ltd.
Type II diabetes is a complex, metabolic disorder char-
acterized by hyperglycemia and subsequent chronic
complications leading to renal failure, blindness, and
coronary artery disease.1 Hyperglycemia in type II dia-
betes is caused by increased insulin resistance and im-
paired insulin secretion from the pancreas.2 The
conventional approach to treat type II diabetes focuses
on the control of blood glucose level in order to reduce
the incidence of the microvascular and macrovascular
complication associated with high blood glucose level.3
The PPARS (peroxisome proliferator-activated recep-
tors) are members of a super family of nuclear receptors
that include steroid, retinoid, and thyroid hormone
receptors.4 These receptors play a pivotal role in regulat-
ing the expression of a large number of genes involved in
lipid metabolism and energy balance.5 It has been shown
that PPARc located in nucleus is able to increase the
insulin sensitivity, promote the differentiation of lipo-
cytes, and retard the occurrence of complications.
Although some PPARc modulators, such as rosiglitaz-
one and pioglitazone (Fig. 1), which have been marketed
as antidiabetes, may cause weight gain, and in some
cases, edema.6 Unsatisfactory efficacy and safety profile
restrict their application, while PPARa agonists have
exhibited lipid lowering activity and reduce weight gain.
Therefore, we were prompted to search for new PPARc
and PPARa dual agonists as novel insulin sensitizers.
By scrutinizing the binding mode of PPARc and
PPARa to the dual agonist AZ-242 (the PDB deposition
numbers were 1I7I and 1I7G) with docking operation
and molecular simulation, and analyzing the 3D-QSAR
of PPARc and PPARa dual agonists, a common U-
shaped pharmacophore model was derived, which was
featured by the presence of an acidic moiety responsible
for hydrogen bonding network on one terminal, a
hydrophobic and bulky fragment on the other end,
and a flat and narrow linker between the two terminals
(Fig. 2).7
Guided by the mutual pharmacophore, the PPARc/a
dual agonists can be divided into three regions: A is
the acidic head group, B is the linker part, and C is
the hydrophobic tail group (Fig. 3). A novel virtual
library of the dual agonists was constructed based on
a combinatorial strategy. The building blocks A–C were
selected from commercially available compounds with
the criteria of drug-like properties, pharmacophoric
requirement, and chemical feasibility. Accordingly, a
virtual library with the capacity of over 1000 com-
pounds was automatically generated from the building
blocks with the Project Library program. The com-
pounds in the resultant virtual library were matched
with the binding pocket of PPARc and PPARa with
the program DOCK5.08 and virtual compounds with
potentially high binding affinity were selected as ÔhitsÕ
based on the scoring system of shape and energies. In
the subsequent synthesis and evaluation of the hit com-
pounds, we found that the para-ethyl biphenoxy 2-meth-
oxydihydrocinnamic acid 1g was a high affinity ligand
Keywords: PPAR agonists; Antidiabetes; 2-Alkoxydihydrocinnamates.
*
Corresponding author. Tel.: +86 10 631 65249; fax: +86 10 831
0960-894X/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2005.10.104