Medicinal Chemistry

(Jacob Rumans) #1
IMMUNOMODULATORS AND THEIR RECEPTORS 403

cancer, hepatitis C, osteoporosis, diabetic foot ulcers, wound care, and muscle wasting.
Drugs based on the neurotrophic growth factors are being developed to treat chronic
pain disorders such as diabetic neuropathy. Small-molecule drugs based on vascular
endothelial growth factors are being developed as anticancer agents, because they
inhibit the ability of the tumor to grow the new blood vessels (angiogenesis) that are
crucial to supporting its rapid rate of growth. The synthesis of such an anti-angiogenesis
agent is given in figure 6.4. Clearly, there are many diseases that can be targeted using
small molecules based on molecular messengers such as interleukins, cytokines, or
growth factors.


6.4 The Clinical–Molecular Interface: Collagen Diseases


The collagen diseases (also known as collagen-vascular diseases, connective tissue
diseases, or rheumatoid diseases) are a group of clinicopathological entities presenting


ZD6474 is one of the many immunomodulating molecules currently in clinical trials for the
treatment of various types of cancers. Its aqueous solubility (330 μM at pH 7.4) and anti-
tumor activity at a dosage as low as 12.5 mg/kg per day in mice made this compound a good
candidate for clinical trials in replacement of the more potent but less bioavailable analog
ZD4190.
Unlike conventional anticancer drugs whose ability to inhibit tumor growth is attributable
to a direct cytotoxic or cytostatic effect on tumor cells, ZD6474 exerts its anticancer activity
by blocking tumor angiogenesis viathe inhibition of the vascular endothelial growth factor
(VEGF) signaling pathway. The total synthesis of the drug candidate ZD6474 (Hennequin
et al., 1999) has been achieved in a twelve-step procedure starting from the readily available
vanillic aldehyde, a naturally occurring catechol derivative that is directly extracted from
vanilla beans (Hocking, 1997) (reaction scheme a).
The alcohol 10 introduced at step j was prepared following a literature procedure from
ethyl-2-(piperidin- 4-yl)acetate after N-Boc protection and selective reduction of the ester
group using lithium aluminum hydride (Villalobos et al., 1994) (reaction scheme b).
References for Figure 6.4
L. F. Hennequin, A. P. Thomas, C. Johnstone, E. S. E. Stokes, A. P. Ple, J.-J. M. Lohmann,
D. J. Ogilvie, M. Dukes, R. S. Wedge, J. O. Curwen, J. Kendrew, C. Lambert-van der
Brempt (1999),J. Med. Chem. 42: 5369–5389.
M. B. Hocking (1997),J. Chem. Educ. 74: 1055–1059.
A. Villalobos, J. F. Blake, C. K. Biggers, T. W. Butler, D. S. Chapin, Y. L. Chen, J. L. Ives,
S. B. Jones, D. R. Liston, A. A. Nagel, D. M. Nason, J. A. Nielsen, I. A. Shalaby, W. F. White
(1994),J. Med. Chem. 37: 2721–2734.

Scheme b
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