Medicinal Chemistry

IMMUNOMODULATORS AND THEIR RECEPTORS 399
Regrettably, the receptor classification system is much more complex than this. For
example, the chemokine class of cytokine receptors is further subdivided into at least
16–20 different receptor subtypes, including CCR1, CCR2 ... CCR11, CXCR1,
CXCR2 ... CXCR5. These receptors interact with more than 25–30 different types of
chemokines.
Complicated though the classes of cytokines and their receptors may be, this explo-
sion of data does offer significant hope that druggable targets can and will be identified
for purposes of drug design. To date, most of the work to develop therapeutics has been
done through a more biological approach; i.e., developing antibodies against cytokine
targets. However, small organic molecules capable of targeting cytokines and cytokine
receptors are beginning to emerge:

1. By screening compound libraries, selective antagonists for the chemokine CCR3
   receptor have been identified; these contain arylpiperidine motifs linked by a 3–6
   carbon tether to a second aromatic group. Such compounds may have utility in treat-
   ing chronic inflammatory disorders such as bronchial asthma.


2. Screening assays are also being used to optimize a series of benzimidazole derivatives
   and a series of 4-pentadienamide derivatives as antagonists for the chemokine CCR2
   receptor. Such compounds may be useful in treating the inflammation that occurs in
   the walls of blood vessels undergoing degenerative atherosclerotic processes.


3. The cytokine TNF-αis synthesized through the actions of the TNF-α-converting
   enzyme (TACE), which cleaves the 76-amino acid TNF-αfrom its 233-amino acid
   precursor. Based upon computer-aided drug design (sequence homology studies)
   and X-ray crystallographic studies, rational drug design is leading to TACE
   inhibitors as potential therapeutics for inflammatory bowel diseases such as ulcera-
   tive colitis or Crohn’s disease.


4. The biosynthesis of the IL-12 cytokine is dependent upon various enzymes, including
   phosphodiesterase 4 (PDE4). Thus, PDE4 enzyme inhibitors act as functional IL-12
   antagonists, and may have clinical application in the treatment of rheumatoid arthritis.


5. Cytokine-suppressing anti-inflammatory drugs (CSAIDs) are a new class of agents
   that inhibit the production of cytokines such as TNF-α. Many prototypic CSAIDs are
   built around a bicyclic imidazole framework and are being optimized through the
   application of quantitative structure–activity relationship studies of analogous series.

An exploration and exploitation of cytokines represents the future of drug design for the
purposes of manipulating the immune messenger systems. Table 6.1 lists a number of
cytokines being pursued as drug design targets. Drugs based upon the biochemistry of
cytokines will have widespread utility in many chronic inflammatory disorders, espe-
cially the collagen-vascular diseases (see section 6.4).

6.3.2 Growth Factors

Just as interferons and interleukins are a subset of the class of molecules known as
cytokines, in turn, cytokines are a subset of a larger family of proteins known as growth
factors (see figure 6.3). Although not all growth factors are involved in regulation of the
immune system, they are nevertheless protein messenger molecules that influence cell