DuP 532: a second generation of nonpeptide angiotensin II receptor antagonists.
DuP 532 is a novel nonpeptide angiotensin II (AII) receptor antagonist under development for the treatment of hypertension. DuP 532 is a more potent antihypertensive agent in renal hypertensive rats (ED30 = 0.042 mg/kg, i.v.) and displays a similar or longer duration of action than the previously described AII antagonist, DuP 753. DuP 532, in contrast to DuP 753, is a noncompetitive antagonist of AII-induced contractions of rabbit aortic strips (KB = 1.1 x 10(-10) M). However, the inhibition of AII binding by DuP 532 in rat adrenal cortex does not correlate with either the aortic contractile response or with the hypotensive response. Assay conditions were evaluated and the presence or absence of BSA was shown to markedly affect the apparent binding affinity of DuP 532 and other 5-carboxylic acid derivatives. DuP 753 and other compounds were much less affected. The IC50 for DuP 532 was 4.7 x 10(-6) M with and 3 x 10(-9) M without BSA. The IC50s for DuP 753 were 1.7 x 10(-8) M with and 5 x -9 M without BSA. Both compounds with or without BSA did not completely inhibit AII binding which is characteristic of AT1 selectivity. BSA also reduced the effect of DuP 532 on the AII-induced contractions of rat main pulmonary artery preparations and the AII-induced Ca2+ mobilization in rat aortic smooth muscle cells. DuP 532 was very specific for AT1 receptors and did not interfere with receptors associated with neurotensin, prazosin, bradykinin, nitrendipine, or vasopressin. It is concluded that DuP 532 represents a new class of specific, but noncompetitive. AII receptor antagonists whose binding characteristics may provide new insight into AII receptor function.
Chiu
A T
AT
Du Pont Merck Pharmaceutical Company, Wilmington, DE 19880-0400.
Carini
D J
DJ
Duncia
J V
JV
Leung
K H
KH
McCall
D E
DE
Price
W A
WA
Wong
P C
PC
Smith
R D
RD
Wexler
R R
RR
Timmermans
P B
PB
D000311:Adrenal Glands / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008861:Microsomes / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D011485:Protein Binding; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D011945:Receptors, Angiotensin / Q000187:drug effects* / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000378:metabolism / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*; D005466:Fluorocarbons
D000804:Angiotensin II; D000959:Antihypertensive Agents; D002118:Calcium; D007093:Imidazoles; D011945:Receptors, Angiotensin; D012710:Serum Albumin, Bovine; D013777:Tetrazoles; C069045:DuP 532; D005466:Fluorocarbons