Bioorganic & Medicinal Chemistry Letters 15 (2005) 195–201
Amino-substituted heterocycles as isosteres of
trans-cinnamides: design and synthesis of heterocyclic biaryl
sulfides as potent antagonists of LFA-1/ICAM-1 binding
Gary T. Wang,* Sheldon Wang, Robert Gentles, Thomas Sowin, Sandra Leitza,
Edward B. Reilly and Thomas W. von Geldern
Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park Rd., Abbott Park, Il 60064, USA
Received 17 September 2004; revised 4 October 2004; accepted 4 October 2004
Abstract—2-Amino-4-phenyl pyridine and, to a lesser extent, 4-amino-6-phenyl pyrimidine, were established as isosteres of trans-
cinnamide moiety. Applying this isosterism to previously reported p-arylthio cinnamides resulted in the identification of 4-
amino-6-(p-arylthio)phenyl-pyrimidines and 2-amino-4-(p-arylthio)phenyl-pyridines as potent antagonists of LFA-1/ICAM-1
binding.
Ó 2004 Elsevier Ltd. All rights reserved.
Adhesion-mediated leukocyte emigration is a mecha-
nism of host defense following inflammation, injury or
infection.1,2 During this process, circulating leukocytes
are attracted to the injury or infection site and cross
the vascular endothelium wall to enter the surrounding
tissues, where the leukocytes neutralize the pathogens
and carry out regulated tissue destruction. However,
over activation of this process leads to untoward tissue
damage, as found in many inflammatory diseases and
reperfusion injury such as ischemia following stroke,
myocardial infarction and trauma. At the molecular
level, the recruitment of leukocytes is primarily mediated
by the interaction between leukocyte-function-associ-
ated antigen-1 (LFA-1, also known as CD11a/CD18
or avb2 integrin) on leukocytes and intercellular adhe-
sion molecule-1 (ICAM-1, also known as CD54) on
endothelial cells.1,2 Thus, inhibition of LFA-1/ICAM-1
binding represents a potential therapeutic target for
these conditions.3
high throughput screening lead, extensive medicinal
chemistry effort led to the identification of several sub-
series of compounds with potent LFA-1/ICAM-1 antag-
onist activity, good solubility and pharmacokinetic
properties.4–7 During the course of the project, the met-
abolic stability of the trans-cinnamide moiety became a
concern, since incubating one analog of p-arylthio trans-
cinnamides with rat and human liver microsomes
resulted in cinnamide isomerization and subsequent deg-
radation. Thus, we undertook an effort to identify
replacements of the trans-cinnamide moiety, even
though it was ultimately proven that the cinnamide
was sufficiently stable. Toward this end, diarylsulfide
trans-cyclopropylamides 3 (Fig. 1) have been reported
by Link et al.8 This class of compounds, in which the
olefin bond of the cinnamide was replaced with a cyclo-
propyl ring, have been shown to have LFA-1/ICAM-1
antagonist activity comparable with the analogous cinn-
amides 1. Alternatively, we envisioned that properly
substituted heterocycles depicted by 4 (Fig. 1), such as
4-amino-6-(p-arylthio)phenyl-pyrimidine or 2-amino-4-
(p-arylthio)phenyl-pyridine, could serve as isosteres of
1. Based on both electronic and steric considerations,
these moieties could potentially replace both the olefin
bond and the carbonyl of the trans-cinnamide moiety.
We report our findings in this paper.
Our laboratories have reported several series of p-aryl-
thio trans-cinnamides, represented by structure 1 and
exemplified by compound 2 (Fig. 1), as potent antago-
nists of LFA-1/ICAM-1 interaction.3 Starting from a
Keywords: trans-Cinnamide isostere; Cell adhesion; LFA-1/ICAM-1
binding.
*
Our attention was first focused on 4-amino-6-(p-aryl-
thio)phenyl-pyrimidines 10 which were synthesized
Corresponding author. Tel.: +1 8479372489; fax: +1 8479355165;
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.10.008