Siegl P K
Merck Research Laboratories, West Point, PA 19486.
J Hypertens Suppl. 1993 Apr;11(3):S19-22.
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.
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.
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.
氯沙坦的发现：氯沙坦（DuP 753，MK 954）是首个强效且选择性的非肽类血管紧张素II（Ang II）拮抗剂。氯沙坦的发现源于一项观察，即几种简单的苄基咪唑是较弱的Ang II拮抗剂。这些化合物（如S8307）效力不足，但口服活性良好且对Ang II受体（AT受体）具有选择性。氯沙坦是以S8307和其他苄基咪唑类似物作为化学先导物合成的。
氯沙坦能选择性抑制所有已研究的Ang II反应，并在几种肾素依赖性高血压动物模型中降低血压。在动物体内，氯沙坦的降压效果与血管紧张素转换酶（ACE）抑制剂相似，但与ACE抑制剂不同的是，氯沙坦是肾素 - 血管紧张素系统更具选择性的抑制剂，因为它不影响激肽的代谢。与肽类Ang II拮抗剂（如沙拉新）相比，氯沙坦具有显著优势，包括作用时间长、口服吸收有效且无Ang II激动剂活性。
氯沙坦对AT受体具有高选择性和强效性、非肽结构以及口服活性，代表了一项药理学突破。该药物目前正用于阐明AT受体的生理学特性，并且可能对已知涉及肾素 - 血管紧张素系统的疾病的治疗管理有用。
