P K Siegl1. 1. Merck Research Laboratories, West Point, PA 19486.
Abstract
DISCOVERY OF LOSARTAN: Losartan (DuP 753, MK 954) is the first potent and selective non-peptide angiotensin II (Ang II) antagonist. The discovery of losartan followed an observation that several simple benzylimidazoles are weak Ang II antagonists. These compounds (e.g. S8307) lack potency but are orally active and selective for Ang II receptors (AT receptors). Losartan was synthesized using S8307 and other analogs of the benzylimidazoles as chemical leads. ACTION OF LOSARTAN: Losartan selectively inhibits all Ang II responses that have been studied and lowers blood pressure in several animal models of renin-dependent hypertension. In animals, the antihypertensive efficacy of losartan is similar to that of angiotensin converting enzyme (ACE) inhibitors but, unlike ACE inhibitors, losartan is a more selective inhibitor of the renin-angiotensin system since it does not affect the metabolism of kinins. Compared with peptide Ang II antagonists (e.g. saralasin), losartan has significant advantages, including a long duration of action, effective oral absorption and no Ang II agonist activity. CONCLUSIONS: The high selectivity and potency for AT receptors, the non-peptide structure and the oral activity of losartan represent a pharmacological breakthrough. This agent is now being used to elucidate the physiology of AT receptors and is likely to be useful in the therapeutic management of diseases in which the renin-angiotensin system is known to be involved.
DISCOVERY OF LOSARTAN: Losartan (DuP 753, MK 954) is the first potent and selective non-peptide angiotensin II (Ang II) antagonist. The discovery of losartan followed an observation that several simple benzylimidazoles are weak Ang II antagonists. These compounds (e.g. S8307) lack potency but are orally active and selective for Ang II receptors (AT receptors). Losartan was synthesized using S8307 and other analogs of the benzylimidazoles as chemical leads. ACTION OF LOSARTAN: Losartan selectively inhibits all Ang II responses that have been studied and lowers blood pressure in several animal models of renin-dependent hypertension. In animals, the antihypertensive efficacy of losartan is similar to that of angiotensin converting enzyme (ACE) inhibitors but, unlike ACE inhibitors, losartan is a more selective inhibitor of the renin-angiotensin system since it does not affect the metabolism of kinins. Compared with peptide Ang II antagonists (e.g. saralasin), losartan has significant advantages, including a long duration of action, effective oral absorption and no Ang II agonist activity. CONCLUSIONS: The high selectivity and potency for AT receptors, the non-peptide structure and the oral activity of losartan represent a pharmacological breakthrough. This agent is now being used to elucidate the physiology of AT receptors and is likely to be useful in the therapeutic management of diseases in which the renin-angiotensin system is known to be involved.