Bioorganic & Medicinal Chemistry Letters 16 (2006) 267–270
Biphenyl-4-ylcarbamoyl thiophene carboxylic acids as potent
DHODH inhibitors
Johann Leban,* Martin Kralik, Jan Mies, Roland Baumgartner,
Michael Gassen and Stefan Tasler
4SC AG, Am Klopferspitz 19a, 82152 Martinsried, Germany
Received 24 June 2005; revised 14 September 2005; accepted 5 October 2005
Available online 21 October 2005
Abstract—A previously discovered DHODH inhibitor series was further improved by replacing the cyclopentene ring by aromatic
heterocycles. Different isomers of these compounds were prepared by the directed ortho-metallation procedure. The compounds are
more active than the corresponding cyclopentene analogs and show potent effects on PBMCÕs proliferation.
Ó 2005 Elsevier Ltd. All rights reserved.
We have developed a novel series of DHODH inhibitors
based on a lead, which came out of a docking procedure
using 4ScanÒ technology and medicinal chemistry
exploration. The activity of the initial lead was im-
proved by a QSAR method and yielded low nanomolar
inhibitors.1
a second carboxylic group, like in C or E, were either
built up by 2-fold DoM/CO2-quenching or from 3,4-thi-
ophene dicarboxylate upon its conversion into the
anhydride with acetic anhydride and nucleophilic anhy-
dride opening with the respective 4-phenylaniline to give
compounds 13–15. Regiochemistry for the carboxylate
introduction in 3-thiophenamides A was in analogy to
a literature protocol4 and was finally deduced from
NMR analysis to be in the 2-position.
Such compounds promise to have great potential as
treatment for autoimmune diseases such as rheumatoid
arthritis, graft versus host disease, and multiple sclero-
sis.2 To further explore the scope of DHODH inhibitors
of types 1–3 (Table 1), a replacement of the cyclopentene
ring with other small aromatic systems was envisaged.
Our X-ray structure indicated that the cyclopentene
ring lies virtually planar in a pocket close to the FAD
cofactor.3 Flat small aromatic rings might therefore
be of benefit for binding and activity.
Introduction of a third carboxylic group into B yielded a
major and a minor component, which were separated by
HPLC. Major product C possessed a completely identi-
cal NMR spectrum as the major product E from carbox-
ylation of 3-thiophene-2-carboxylate D by the DoM
protocol. Therefore, the structure has to be as depicted
in Figure 1.
Compound B (Fig. 1) was synthesized by the directed
ortho-metallation procedure (DOM)4 at the stage of
the amide using butyl lithium and dry ice as CO2 source
for the introduction of the carboxylic group. Thiophene
amides A were prepared from commercial 3-thiophene-
carboxylic acid by conversion into the acid chloride
and reaction with the corresponding 4-phenylaniline,
which in turn were obtained by the Suzuki cross-
coupling method as described earlier.1 Compounds with
Enzyme inhibition was measured in an in vitro enzyme
assay. For the assay N-terminally truncated recombi-
nant human DHODH was used and the data are pre-
sented in Table 1.5
Direct comparison of the previously described com-
pounds 1–3 with their thiophene analogs 4, 5, and 8
showed a clear trend toward an increased inhibitory
activity of the thiophene analogs. As with the cyclopen-
tene series, the activity increases with fluoro constituents
in the aromatic ring adjacent to the amide bond and
with a methoxy group in the terminal aromatic, but
the trend is more pronounced in the thiophene series.
A X-ray structure investigation of the cyclopentene
Keywords: DHODH inhibitors.
*
Corresponding author. Tel.: +49 89 700763 0; fax: +49 89 700 763
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.10.011