Nonpeptide angiotensin II receptor antagonists: synthetic and computational chemistry of N-[[4-[2-(2H-tetrazol-5-yl)-1-cycloalken-1- yl]phenyl]methyl]imidazole derivatives and their in vitro activity.
A series of nonpeptide angiotensin II receptor antagonists was synthesized and tested in vitro to investigate requirements for recognition by and binding to AT1 receptors. Compared to a known series of N-(biphenylylmethyl)imidazoles, including losartan (DuP 753), which has a more rigid conformation in the 2'-tetrazolylbiphenyl moiety, the new series replaces the terminal phenyl with cycloalkenyls. Compounds were made with five- to seven-membered rings and with either a hydroxymethyl (3) or carboxyl (4) group at the 5 position on the imidazole ring. The effects of the lipophilicity and steric bulk of the terminal ring system, the amount of pi-electron density in the terminal ring, and the relative spatial proximity of the tetrazolyl and the middle phenyl are explored in terms of binding affinity to AT1 receptors in rat adrenal glomerulosa and rabbit aorta. The physicochemical variables of the new compounds were quantitated by computational chemistry and compared to those of losartan and its carboxyl metabolite. Potency at the AT1 receptors is maximized when the terminal ring is six-membered; an aromatic ring binds better than a cycloalkenyl ring. The 5-carboxyimidazole compounds show higher affinity than the 5-hydroxymethyl series.
Lin
H S
HS
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
Rampersaud
A A
AA
Zimmerman
K
K
Steinberg
M I
MI
Boyd
D B
DB
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D019808:Losartan; D008297:Male; D008958:Models, Molecular; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D019808:Losartan