Antihypertensive Losartan Research Articles

How the antihypertensive losartan was discovered

Based on interviews and publications, this case study is a history of how DuPont scientists discovered losartan, the first angiotensin II receptor antagonist. Essential aspects of the story include: i) the discovery occurred at a young and inexperienced pharmaceutical business; ii) three bench scientists had recently graduated from PhD programmes and only the fourth had any industrial research experience; iii) pivotal to its success was the support and risk-taking of the highly experienced and recently hired head of pharmaceutical research; iv) a timely patent issued to Takeda Chemical Industries suggested a new line of research; v) a mistake made by an inexperienced pharmacologist yielded pivotal information; vi) the bench scientists were given the freedom to explore while being supported by research managers; vii) luck favoured the scientists in losartan’s subreceptor-binding and metabolite; and viii) the marketing group insisted that losartan not be developed until Merck expressed an interest in the drug candidate. Today, losartan is a multibillion dollar drug.

4'-(2-Butyl-4-chloro-5-formylimidazol-1-ylmethyl)biphenyl-2-carbonitrile

The title compound, C22H20ClN3O, (I), is used as an inter­mediate for the synthesis of the antihypertensive drug losartan. Bond lengths and angles are unexceptional. The crystal packing is stabilized by one C—H⋯O and one C—H⋯N contact. It is noteworthy that (I) is isomorphous with a closely related compound which differs in having a but-2-en­yl chain instead of a but­yl chain on the imidazole ring.

Losartan and fetal toxic effects

We report a case of maternal exposure to the antihypertensive drug losartan during weeks 20-31 of pregnancy. We saw the fetal toxic effects of oligohydramnios (decreased amniotic fluid), fetal pulmonary hypoplasia, fetal hypoplastic skull bones, and subsequent fetal death. This pattern of abnormalities is similar to those seen in exposure to angiotensin-converting-enzyme (ACE) inhibitors during pregnancy, and were probably caused by losartan.

Encapsulation of Commercially Available Losartan for Blinding Purposes Does Not Affect its Bioavailability

When developing any new drug for an established therapeutic area, it is important to show that the new drug is as effective as, or superior to, pre-existing therapies. The credibility of comparative studies is dependent on them being carried out in an unbiased fashion. It is generally a prerequisite that such studies are conducted in a double-blind manner, which often involves the use of the doubledummy technique, where matching active and placebo preparations are given in combination.[1] If the matching placebo preparations are not readily available, alternative methods of blinding the study medication have to be considered, for example enclosing active and placebo test medications in capsules to make them identical in appearance.[2] However, it is important to verify that the properties of the original preparation have not been altered by the encapsulation, through in vitro and/or in vivo investigations. Commercially available tablets of the antihypertensive drug losartan[3] were encapsulated for use in a comparative double-blind clinical trial.[4] The in vitro dissolution and chemical stability of the original tablets have previously been found to remain unchanged following encapsulation (data on file). The purpose of the present study was to investigate whether encapsulation affects the bioavailability of losartan. Bioequivalence of the encapsulated and standard (i.e. nonencapsulated) tablets was, therefore, evaluated following single dose administration in healthy volunteers.

Differential structural requirements for specific binding of nonpeptide and peptide antagonists to the AT1 angiotensin receptor. Identification of amino acid residues that determine binding of the antihypertensive drug losartan

The biphenylimidazole derivative losartan exemplifies a novel class of nonpeptide antagonists that selectively inhibit angiotensin II binding to the mammalian AT1 receptor and have potentially wide application as anti-hypertensive agents. In contrast to mammalian AT1 receptors, which have high affinity for both peptide antagonists and losartan, amphibian and avian angiotensin II receptors are pharmacologically distinct and recognize peptide but not nonpeptide antagonists. Mutant rat AT1 receptors in which non-conserved amino acids were replaced by the corresponding amphibian residues were constructed to identify specific sites in the AT1 receptor that determine losartan binding. Only minor changes in binding affinity for peptide antagonists were observed in COS-7 cells transiently expressing mutant receptors, indicating that the structural integrity of the receptor was maintained. However, analysis of receptors with single point and combined mutations revealed that specific residues in transmembrane domains III, IV, V, VI, and VII are involved in binding of the nonpeptide antagonist to the mammalian AT1 receptor. The most marked attenuation of losartan binding (IC50 > 50 microM) was observed in a mutant receptor containing amino acid substitutions at Val108, Ala163, Thr198, Ser252, Leu300, and Phe301. These results have demonstrated that the binding site of a potent nonpeptide antagonist of the AT1 receptor is defined by epitopes located within the membrane-spanning regions of the receptor and is distinct from the site at which peptide antagonists bind to the AT1 receptor.