angiotensin receptor antagonists are active only during continuous intravenous infusion,
and are therefore seldom if ever used.
A more recent class of nonpeptidic angiotensin II antagonists has been designed and
developed. These are potent, orally active, specific, competitive inhibitors of the AT 1
receptor and exhibit blood pressure lowering efficacy analogous to that of enalapril. Rep-
resentative congeners in this class of compounds include losartan (5.146), valsartan
(5.147), eprosartan (5.148), candesartan (5.149), and irbesartan (5.150). Losartan was
designed with the aid of computer modeling studies in which the structure of angiotensin
II was overlapped with a series of antihypertensive imidazole-5-acetic acid analogs.
5.22 PEPTIDE HORMONES OF THE HEART
(NATRIURETIC FACTORS)
In 1981, De Bold and his co-workers discovered that extracts of heart atria (but not
ventricles) cause profound natriuresis, diuresis, and hypotension in rats. It was found
that secretory granules in the atria contain a series of peptides responsible for these
homeostatic regulatory effects, and that the heart is de facto an endocrine organ—a
landmark observation. These atrial natriuretic peptides (ANP) are derived from a pro-
hormone (preproANP) consisting of 151 amino acids that is produced in response
to atrial stretch, high blood volume, and high sodium concentration. The prohormone
is subsequently modified and cleaved into shorter segments. ANP circulates as a
28-amino-acid peptide with a single disulphide bridge that forms a 17-residue ring.
376 MEDICINAL CHEMISTRY