Modern Drug Discovery Home Page

Table of Contents

November-December 1998
Volume 1, Number 2

FEATURES

20	Nitric oxide-releasing compounds: From basic research to promising drugs By attaching NO-releasing functional groups to carrier molecules, new biomedical research tools and potential clinical agents that spontaneously generate bioactive nitric oxide have been made possible. Larry K. Keefer
31	From hypertension to angina to Viagra Jim Kling On its way to becoming Viagra, UK-92,480 changed from a drug for hypertension to a drug for angina, and then changed again when a 10-day toleration study in Wales turned up an unusual side effect.
41	Rational drug design: Controlling the size of the haystack Donald B. Boyd Combinatorial chemistry creates larger and larger haystacks in which to find the needle. Rational design attempts to focus the design process on the smallest possible set of viable compounds.
49	Illuminating the SNP genomic code Anthony W. Czarnik Most DNA sequence differences between any two humans are single base pair differences, or single nucleotide polymorphisms (SNPs). A fiber-optics-based technology for SNP detection is a new tool for discovery of genes influencing complex traits and new drug development targets.

DEPARTMENTS

7	Editorial
9	Letters
11	In Brief This year's flu A connection between secretin and autism? Relief for sufferers of rheumatoid arthritis Surfers beware
14	Analysis The human genome: A race to the finish?
57	Reviews Her-2: The Making of Herceptin, a Revolutionary Treatment for Breast Cancer The Excruciating History of Dentistry: Toothsome Tales & Oral Oddities from Babylon to Braces
59	New Products
62	Meetings
63	Ad Index
64	EtCetera

ON THE COVER

cGMP, Zaprinast, and Viagra (sildenafil) illustrate the molecular evolution described in our story on Viagra. Viagra, an inhibitor of phoshodiesterase 5 (PDE 5), was discovered by using a rational drug design approach. As explained in Jim Kling's article, Pfizer chemists began their quest for a PDE inhibitor by comparing structures of cGMP (top), a substrate of some PDEs, a Zaprinast (middle), which was one of the few know PDE inhibitors in 1986. Structural comparisons suggested a line of experimentation that eventually led to Viagra (bottom). Cover illustration by gh multimedia.