Discovery of losartan, the first angiotensin II receptor antagonist.
The 'discovery' of losartan represents three separate discoveries: (1) losartan as the unique biphenyltetrazole molecule and the first of a new chemical class; (2) losartan as a tool to identify AT1-subtype receptors; and (3) losartan as a specific probe for exploring the multiple roles of angiotensin II (Ang II) in normal physiology and pathologic states. Losartan is the first nonpeptide orally active Ang II receptor antagonist to reach clinical trials. Losartan was selected for its affinity for Ang II receptors, functional antagonism of Ang II, lack of agonist properties, and oral anti-hypertensive effects. Losartan has been widely used to define the distribution and function of AT receptor subtypes. Although possible roles of the AT2 subtype have been reported, virtually all of the known effects of Ang II are blocked by losartan. Specific AT1 receptor blockade has been broadly compared with ACE inhibition. Possible differences on the basis of AT1 selectivity, bradykinin potentiating effects and Ang II formed by non-ACE pathways are discussed. Losartan blocks the vascular constrictor effect of Ang II, the Ang II-induced aldosterone synthesis and/or release, and the Ang II-induced cardiovascular 'growth' in vitro and in vivo. In various models of experimental hypertension, losartan prevents or reverses the elevated blood pressure and the associated cardiovascular hypertrophy similar to ACE inhibitors. Likewise, in models of renal failure (for example reduced renal mass, puromycin, ochratoxin), losartan, like ACE inhibition, markedly reduced the elevation in blood pressure, proteinuria or sclerosis. In aortocaval shunt, coronary ligation and ventricular pacing models of heart failure, losartan demonstrated a pathological role for Ang II by reversing the associated haemodynamic findings. In SHR-stroke prone, losartan dramatically increased survival while having a limited effect on blood pressure, suggesting a non-pressure dependent effect of Ang II. These collective data show that Ang II exerts complex pathological effects in experimental models of vascular, cardiac, renal and cerebral disease. The effectiveness of losartan in experimental models of heart failure supports its evaluation in clinical trials with patients with heart failure.
Timmermans
P B
PB
Discovery Research, DuPont Merck Pharmaceutical Company, Wilmington, DE 19800-0400, USA.
Duncia
J V
JV
Carini
D J
DJ
Chiu
A T
AT
Wong
P C
PC
Wexler
R R
RR
Smith
R D
RD
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D019808:Losartan; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D019808:Losartan