Non-peptide angiotensin II receptor antagonists. 1. Design, synthesis, and biological activity of N-substituted indoles and dihydroindoles.
A series of N-acylated indoles (12-18), N-alkylated indoles (19-24), N-acylated dihydroindoles (26-30), and N-alkylated dihydroindoles (31-34) were synthesized and evaluated in the in vitro AT1 (rabbit aorta) and AT2 (rat midbrain) binding assay. The carboxylic acid 3-[[N-(2-carboxy-3,6-dichlorobenzoyl)-5-indolyl]methyl]-5,7-dimeth yl- 2-ethyl-3H-imidazo[4,5-b]pyridine (14b) was found to be the most potent AT1 (IC50 = 0.8 nM) antagonist in the N-acylated indole series and displayed a 25-fold higher potency than the parent unsubstituted derivative 14a (AT1 IC50 = 20 nM) and a 22-fold greater potency than the corresponding dihydroindole analog 27 (AT1 IC50 = 18 nM). Replacement of the terminal carboxyl (COOH) of 14a with the bioisostere tetrazole in 16 (AT1 IC50 = 5 nM, AT2 IC50 = 130 nM) not only improved the AT1 potency by 4-fold but also resulted in a 50-fold increase in AT2 activity. In the N-alkylated indole series, the tetrazole 3-[[N-(2-tetrazol-5-yl-6-chlorobenzyl)-5- indolyl]methyl]-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine (24) exhibited the highest AT1 (IC50 = 1 nM) activity, revealing a 230-fold increase in AT1 activity as a result of the incorporation of the isosteric tetrazole for the carboxyl (COOH) of 20 and a nearly 9-fold increase over the corresponding deschloro analog 22 (AT1 IC50 = 8.7 nM). Tetrazole 34 was identified as the most potent (AT1 IC50 = 18 nM) AT1 receptor antagonist in a structurally distinct series of compounds derived from N-alkylation of dihydroindole 25. A new class of highly potent (14b, AT1 IC50 = 0.8 nM; 24, AT1 IC50 = 1 nM) AT1-selective non-peptide AII receptor antagonists derived from N-substituted indoles and dihydroindoles is disclosed. Tetrazole 24 of the N-alkylated indole series displayed good in vivo activity by blocking the AII-induced pressor response for 5.5 h after intravenous administration in conscious normotensive rats at a 1.0 mg/kg dose level.
Dhanoa
D S
DS
Merck Research Laboratories, Rahway, New Jersey 07065.
Bagley
S W
SW
Chang
R S
RS
Lotti
V J
VJ
Chen
T B
TB
Kivlighn
S D
SD
Zingaro
G J
GJ
Siegl
P K
PK
Patchett
A A
AA
Greenlee
W J
WJ
D015059:1-Sarcosine-8-Isoleucine Angiotensin II / Q000378:metabolism; D000215:Acylation; D000478:Alkylation; D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001565:Benzoates; D001794:Blood Pressure / Q000187:drug effects; D015195:Drug Design; D007093:Imidazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D008636:Mesencephalon / Q000378:metabolism; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011945:Receptors, Angiotensin / Q000378:metabolism; D013329:Structure-Activity Relationship
D057911:Angiotensin Receptor Antagonists; D001565:Benzoates; D007093:Imidazoles; D007211:Indoles; D011725:Pyridines; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C085080:3-((N-(2-tetrazol-5-yl-6-chlorobenzyl)-5-indolyl)methyl)-5,7-dimethyl-2-ethyl-3H-imidazo(4,5-b)pyridine; D015059:1-Sarcosine-8-Isoleucine Angiotensin II