2738
J. P. D. van Veldhoven et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2736–2739
8 Å
7.3 Å
Figure 1. Aligned pharmacophore model (left—nicotinic acid in plane, right—nicotinic acid 90° rotated) constructed of the active compounds nicotinic acid, 6, 11 and 28 and
the inactive compound 10. Red: nicotinic acid, green: cinnamic acid (28), gray: phenyl fumarate (10), blue: butyl fumarate (6), yellow: benzyl fumarate (11).
commercially available aromatic substituted trans propenoic acids
were tested for their affinities (29–43). Only the 4-hydroxy deriv-
ative 35 was able to bind with an affinity of 14 lM. Related substit-
In conclusion, methyl fumarate, ethyl fumarate and cinnamic
acid have been published as agonists for the HCA2 receptor.14,20
Our synthetic program confirmed the affinity of these compounds
for the HCA2 receptor and further explored the structure–activity
relationships for a series of derivatives. Molecular modeling stud-
ies and the analysis of the structure–activity relationships in the
series suggest a planar trans-propenoic acid pharmacophore with
a maximum length of 8 Å and out-of-plane orientation of the larger
substituents
uents such as 4-methoxy (38) and 4-amino (39) decreased the
affinity dramatically. In general, except for the 4-hydroxy group,
aromatic substitution is not tolerated on the ortho, meta or para po-
sition. Also substituents at the b-position of cinnamic acid (44–46)
resulted in a dramatic decrease in binding. Replacement of the
phenyl moiety in cinnamic acid by aromatic isosteres such as 3-
pyridinyl (48) and 2-pyrrole (49) resulted in a significant loss of
affinity. On the contrary, 2-furanyl (51) and 2-thiophenyl (56) were
accommodated like the phenyl compound. 3-Furanyl substitution
(50) resulted in a two-fold decrease compared to the 2-furanyl
derivative 51. As in the cinnamic acid series, the 5-substituted 2-
furanyl derivatives (52–55) and both the 3-bromo and 4-bromo-
substituted 2-thiophenyl derivatives (57, 58) were devoid of affin-
ity for the receptor.
Acknowledgments
This work was performed within the framework of the Dutch
Top Institute Pharma project D1-105.
Supplementary data
To visualize the SAR, a pharmacophore model was generated by
manually superimposing the minimized structures of: nicotinic
acid, cinnamic acid 28, fumaric acid esters 6 and 11, and the inac-
tive phenylfumaric acid ester 10 (Fig. 1). The alignment of the two
sp2 carbons of the propenoic fragment, which all the compounds
have in common, resulted in a planar and constrained pharmaco-
phore. The carbonyl oxygen of the ester function of compounds
6, 10 and 11 and the nitrogen of nicotinic acid overlay smoothly
as a hydrogen acceptor region. This might explain the improved
binding characteristics of the fumaric acid esters compared to cin-
namic acid and also why the trans configuration is superior over
the cis substituted propenoic acids. Molecular modeling and anal-
ysis of the structure–activity relationships in the series suggest a
planar trans-propenoic acid pharmacophore with a maximum
length of 8 Å, because this is the size of the largest planar ligand
(28) in our series with appreciable affinity for the receptor. Larger
compounds need an out-of-plane orientation as in the case of the
fumaric acid ester series (2–24).
Supplementary data (reaction schemes and experimental data)
associated with this article can be found, in the online version, at
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a,b-position was maintained, as in tetrahydro-anthranilic acids,
the planar orientation and also the affinity was regained however.22