Historical development of saralasin.

The research environment in which saralasin was discovered has been described, and illustrations of the rationale which contributed to its synthesis, selection for development, and eventual development have been presented. As an example, the synthesis of [Sar1, Val5, Ala8]-AII (P113, saralasin) was an attempt to make an AII antagonist which would be resistant to metabolism by aminopeptidases. Subsequent evaluation, however, indicated that the substitution of sarcosine had not only protected against aminopeptidase degradation but unexpectedly also had greatly increased the octapeptide's affinity for vascular smooth muscle receptors. Finally, the laboratory demonstration of saralasin as a potential therapeutic and diagnostic entity and the clinical confirmation of use of saralasin in hypertensive patients are reviewed.