The Development of Potent Angiotensin II Receptor Antagonists Using a Novel Peptide Pharmacophore Model

The renin-angiotensin system plays a key role in the regulation of blood pressure, fluid and electrolyte balance, and blood volume. In the initial step of the biochemical cascade, the proteolytic enzyme renin catalyzes the breakdown of the high-molecular-weight peptide, angiotensinogen, to angiotensin I. The report of the benzylimidazole 1 sparked our interest in the application of an overlay hypothesis strategy to aid in the design of nonpeptide angiotensin II antagonists. Careful examination of existing AII peptide structure-activity relationship helped refine our overlay hypothesis strategy and focus our synthetic efforts. Thus, a Tyr-Phe overlay hypothesis became the focus of our molecular modeling efforts. According to this overlay hypothesis, the small molecule covered the Tyr aromatic ring, Ile sidechain, and the Phe carboxylate of AII but failed to reach other regions of the octapeptide known to be important for affinity, such as the Arg and His sidechains and Phe aromatic ring.