(Dipropylphenoxy)phenylacetic acids: a new generation of nonpeptide angiotensin II receptor antagonists

Dhanoa, Daljit S.; Bagley, Scott W.; Chang, Raymond S.L.; Lotti, Victor J.; Chen, Tsing Bau; Kivlighn, Salah D.; Zingaro, Gloria J.; Siegl, P. K. S.; Chakravarty, Prasun K.

doi:10.1021/jm00075a033

Cited by 16 publications

(10 citation statements)

References 7 publications

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“…Enhanced AT 2 binding potency has also been reported in AT 1 -selective antagonist series in which the biphenyltetrazole moiety is replaced by a phenoxyphenylacetic acid ( 9 : AT 1 IC 50 = 19 nM; AT 2 IC 50 = 240 nM), , related (phenylamino)phenylacetic acid ( 10 : AT 1 IC 50 = 5.3 nM; AT 2 IC 50 = 490 nM), or a substituted indole element ( 11 : AT 1 IC 50 = 5 nM; AT 2 IC 50 = 130 nM) 19 Balanced antagonists with biphenyl replacements. …”

Section: Balanced Angiotensin II Antagonistsmentioning

confidence: 90%

Nonpeptide Angiotensin II Receptor Antagonists: The Next Generation in Antihypertensive Therapy

et al. 1996

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Section: Balanced Angiotensin II Antagonistsmentioning

confidence: 90%

Nonpeptide Angiotensin II Receptor Antagonists: The Next Generation in Antihypertensive Therapy

et al. 1996

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“…The secondary hydroxy group of 21 - D + C was protected as a TBS ether, and bis(silyl ether) 22 - D + C was subjected to ozonolysis in the presence of pyridine . Subsequent Horner–Wadsworth–Emmons (HWE) olefination with phosphonate 23 (prepared from methyl 4-allyloxybenzoate 25 by Blanc chloromethylation, followed by the Michaelis–Arbuzov reaction of the resultant 26 ) afforded olefinated product 24-D containing the benzoic acid moiety. Olefin 24-D was obtained as a single stereoisomer.…”

Section: Resultsmentioning

confidence: 99%

Stereoselective Synthesis of the Tricyclic Core of (−)-Callophycoic Acid A

et al. 2020

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Two stereocontrolled routes to the tricyclic core of (−)-callophycoic acid A are described. Our synthetic strategy relied on stereoselective allylboration using a new allylboronate reagent to construct the all-carbon quaternary stereocenter in the core, followed by efficient radical cyclization or palladium-catalyzed reductive cyclization to form its multisubstituted cyclohexane ring. The tetrahydrooxepin ring was constructed by intramolecular etheration. This study provides the first method for the stereoselective synthesis of the characteristic tricyclic skeleton of callophycoic acids.

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“…1 Conditions: (a)PhCOCI,EtsN,DMAP,CHjClj(96%);(b)NBS, AIBN, CCU, reflux (78%); (c) the routes described in the synthetic Schemes I-V. The N-acylated (12-18) and N-alkylated (19)(20)(21)(22)(23)(24) indole and dihydroindole (25) derivatives were prepared from a common intermediate, 13, which is linked to a heterocyclic moiety through a methylene group (Scheme I). The synthesis of 13 begins with the N-benzoylation of 5-methylindole (8).…”

Section: Chemistrymentioning

confidence: 99%

“…3-[[N-(2-Tetrazol-5-ylbenzyl)-5-indolyl]methyl]-5,7-dimethyl-2-ethyl-3H-imidazo [4,5-b]pyridine (22). The title tetrazole 22 was prepared in 55% yield from 21 using method D: R¡= 0.27 (80:20:2 chloroform/methanol/NH4OH); NMR (CDg-OD) 7.76 (s, 1H), 7.73 (d, 1H), 7.39 (t, 1H), 7.32 (d, 1H), 7.12 (d, 1H), 7.10 (d, 1H), 7.01 (s, 1H), 6.92 (dd, 1H), 6.73 (d, 1H), 6.41 (d, 1H), 5.69 (s, 2H), 5.60 (s, 2H), 2.87 (q, 2H), 2.62 (s, 3H), 2.61 (s, 3H), 1.22 (t, 3H); FABMS m/e 463 ( + 1).…”

Section: -[mentioning

confidence: 99%

Non-peptide angiotensin II receptor antagonists. 1. Design, synthesis, and biological activity of N-substituted indoles and dihydroindoles

Dhanoa¹,

Bagley²,

Chang³

et al. 1993

J. Med. Chem.

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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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(Dipropylphenoxy)phenylacetic acids: a new generation of nonpeptide angiotensin II receptor antagonists

Cited by 16 publications

References 7 publications

Nonpeptide Angiotensin II Receptor Antagonists: The Next Generation in Antihypertensive Therapy

Nonpeptide Angiotensin II Receptor Antagonists: The Next Generation in Antihypertensive Therapy

Stereoselective Synthesis of the Tricyclic Core of (−)-Callophycoic Acid A

Non-peptide angiotensin II receptor antagonists. 1. Design, synthesis, and biological activity of N-substituted indoles and dihydroindoles

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