7 Molecular Modifications among Antihypertensive Agents CHESTER J . CAVALLITO
Downloaded by UNIV OF CALIFORNIA SAN DIEGO on January 4, 2016 | http://pubs.acs.org Publication Date: January 1, 1964 | doi: 10.1021/ba-1964-0045.ch007
Neisler Laboratories, Inc., Decatur, Ill.
The historical development of antihypertensive agents is reviewed, with particular attention to the part played by molecular modification in evolving useful drugs. 15 years
many
thousands
During the past of
new
organic
compounds have been prepared and tested in order to provide the handful of antihypertensive agents currently in use. Molecular modifications of prototype structures have yielded anywhere from little or no to moderate to significant improvements in antihypertensive drugs. In each instance the ultimate degree of success was unpredictable prior to the synthesis and ular
testing
of
structural
variants.
Molec-
modifications of drugs and the eluci-
dation of their mechanisms of action are complementary activities, each of which can contribute to the other and to the development of better drugs.
However, at our present state of
knowledge we will probably need to depend for some
time
primarily on the continued
molecular creations of the medicinal chemists for our progress in drug therapy.
increasing attention has been given to the cardiovascular diseases and to hypertensive disease in particular. During the past 15 years the development of improved drugs for use in hypertension has been coupled with an increasing medical awareness of the value of drug therapy in hypertensive disease. M y purpose now is to outline briefly some of these drug developments and to illustrate associated processes of molecular modifications. Some of the older antihypertensive agents such as the nitrites, nitrate esters, thiocyanates, and crude plant products are not considered in this discussion of molecular modifications. 77 In Molecular Modification in Drug Design; Schueler, Fred W.; Advances in Chemistry; American Chemical Society: Washington, DC, 1964.
MOLECULAR MODIFICATION IN DRUG DESIGN
78
One of the principal pharmacological routes followed in the continuing search for useful antihypertensive agents has been selective modulation of the functioning of the autonomic nervous system. Among the earliest synthetic chemical developments in this direction were the sympatholytic or adrenolytic agents. Thirty years ago, Fourneau and Bovet (12) described some synthetic benzodioxanes (I) with adrenolytic properties. During the next 20 years, a variety of chemical types of adrenergic blocking agents were prepared and
Downloaded by UNIV OF CALIFORNIA SAN DIEGO on January 4, 2016 | http://pubs.acs.org Publication Date: January 1, 1964 | doi: 10.1021/ba-1964-0045.ch007
.0
C0- O cH2
I. Piperoxan
studied, among which the more interesting have been the imidazolines (15, 39) CH -^~\ \=/\ 3
fi ( V w
^ C
^N—CH H
2
I
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