α-D-glucuronic acid,α-L-iduronic acid,α-D-glucosamine, and N-acetyl-α-D-glucosamine.
These monosaccharide units are partially sulfated and linked into a polymer via 1–4 link-
ages. The pharmacological activity of heparin is dependent upon a protein, antithrombin
III (AT III), which occurs naturally within the blood plasma. Antithrombin III inhibits
enzymes that are called clotting factor proteases. In doing so, antithrombin III “thins the
blood,” acting as an anticoagulant. Heparin binds to antithrombin III, producing a confor-
mational change that better exposes the antithrombin active site; in doing so, heparin cat-
alyzes the antithrombin–protease reaction without itself being consumed. Through this
mechanism, heparin acts as a potent, intravenously administered anticoagulant (warfarin is
the principal orally administered anticoagulant). Low-molecular-weight (LMW) heparins
are fragments or fractions of commercial-grade heparin. LMW heparins have higher
anticoagulant potency in whole blood than standard heparin. Enoxaparin and dalteparin
are two LMW heparins that are clinically employed.
Although carbohydrates have not traditionally enjoyed a favored status as drug discov-
ery leads, there is room for optimism concerning the future. Research on carbohydrates is
undergoing considerable growth. Computational chemistry (molecular mechanics and ab
initiomolecular orbital calculations), as applied to carbohydrate chemistry, is improving.
Likewise, progress is being made in the synthesis of peptides. Many carbohydrates of cur-
rent medical interest are expressed on cell surfaces as glycoconjugates, including glycol-
ipids, glycosaminoglycans, and glycoproteins. These various cell-surface glycoconjugates
help to promote cell–cell recognition and cell–cell adhesion.
In cell–cell adhesion,lectinsare important; these are carbohydrate binding proteins.
Selectinsare a family of glycoprotein lectins that are implicated in the adhesion of
white blood cells and platelets to the lining of blood vessels. As such, they play a role
in blood clotting and inflammation. Drugs that target selectin receptors are being stud-
ied as putative immunological and anti-inflammatory agents. Since adhesion is also
important to the spread of cancer cells through the process of metastasis, drugs that target
specific cell-surface carbohydrates may also be of therapeutic value in the future.
8.7 Heterocycles as Drugs and Drug Design Targets
Drug molecules should be small, conformationally constrained structures that are rich
in functional groups (e.g., ammonium, carboxylate) and/or hetero-atoms (e.g., N, O, S)
that are capable of establishing energetically favorable intermolecular interactions
between the drug and its receptor. Not surprisingly, heterocyclic compounds are ideal
drug candidates. As discussed at the beginning of this chapter, heterocycles are cyclic
organic molecules that contain heteroatoms other than simply carbon and hydrogen.
The organic chemistry classification of heterocycles was given in section 8.1.6. From a
medicinal chemistry perspective, heterocycles may be functionally divided as follows:
- Endogenous heterocycles
- Natural product exogenous (exogenous to humans, but endogenous to other life forms)
heterocycles - Semisynthetic heterocycles
- Synthetic heterocycles
Each of these four categories is rich in drug discovery lead candidates.
ENDOGENOUS MACROMOLECULES 529