| Non-peptide angiotensin II receptor antagonists. 1. Design, synthesis, and biological activity of N-substituted indoles and dihydroindoles. | |
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MedLine Citation:
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PMID: 8277505 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Comparative Study; Journal Article |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 36 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 1993 Dec |
Date Detail:
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Created Date: 1994-02-04 Completed Date: 1994-02-04 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 4230-8 Citation Subset: IM |
Affiliation:
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Merck Research Laboratories, Rahway, New Jersey 07065. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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1-Sarcosine-8-Isoleucine Angiotensin II
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metabolism Acylation Alkylation Angiotensin II / pharmacology Animals Aorta / metabolism Benzoates Blood Pressure / drug effects Drug Design Imidazoles / chemical synthesis*, metabolism, pharmacology Indoles / chemical synthesis*, metabolism, pharmacology Kinetics Mesencephalon / metabolism Molecular Structure Pyridines / chemical synthesis*, metabolism, pharmacology Rabbits Rats Receptors, Angiotensin / antagonists & inhibitors*, metabolism Structure-Activity Relationship |
| Chemical | |
Reg. No./Substance:
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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 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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