Document Detail

Non-peptide angiotensin II receptor antagonists. 1. Design, synthesis, and biological activity of N-substituted indoles and dihydroindoles.
MedLine Citation:
PMID:  8277505     Owner:  NLM     Status:  MEDLINE    
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.
D S Dhanoa; S W Bagley; R S Chang; V J Lotti; T B Chen; S D Kivlighn; G J Zingaro; P K Siegl; A A Patchett; W J Greenlee
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  36     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1993 Dec 
Date Detail:
Created Date:  1994-02-04     Completed Date:  1994-02-04     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  4230-8     Citation Subset:  IM    
Merck Research Laboratories, Rahway, New Jersey 07065.
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MeSH Terms
1-Sarcosine-8-Isoleucine Angiotensin II / metabolism
Angiotensin II / pharmacology
Aorta / metabolism
Blood Pressure / drug effects
Drug Design
Imidazoles / chemical synthesis*,  metabolism,  pharmacology
Indoles / chemical synthesis*,  metabolism,  pharmacology
Mesencephalon / metabolism
Molecular Structure
Pyridines / chemical synthesis*,  metabolism,  pharmacology
Receptors, Angiotensin / antagonists & inhibitors*,  metabolism
Structure-Activity Relationship
Reg. No./Substance:
0/Benzoates; 0/Imidazoles; 0/Indoles; 0/Pyridines; 0/Receptors, Angiotensin; 11128-99-7/Angiotensin II; 145303-66-8/3-((N-(2-tetrazol-5-yl-6-chlorobenzyl)-5-indolyl)methyl)-5,7-dimethyl-2-ethyl-3H-imidazo(4,5-b)pyridine; 9088-01-1/1-Sarcosine-8-Isoleucine Angiotensin II

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