Several nonsedative H 1 inhibitors have been marketed—for example, astemizole
(4.149) and terfenadine (4.150). They are quite polar molecules and therefore cannot
cross the blood–brain barrier to reach central histamine receptors. This is a good
example of drug design exploiting knowledge of the pharmacokinetic processes to
preclude undesirable CNS side effects.
4.6.4.2 H 2 Antagonists
Antagonists of the H 2 receptor were first reported in 1972 by Black and co-workers, and
work in this area was successively continued by the same group in an elegant series of
investigations based on considerations that were guided by molecular pharmacological
principles. One of the compounds that showed weak H 2 -antagonist activity, guanyl-
histamine, was the point of departure in the development of these drugs. Extension of
the side chain was found to increase the H 2 -antagonist activity, but some agonist effects
were retained. When the very basic guanidino group was replaced by the neutral
thiourea, burimamide (4.151) was obtained. Although an effective drug, it cannot be
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