1H-1,2,4-triazole angiostensin II receptor antagonists: “qC-linked”q analogs of SC-50560

Reitz, David B.; Penick, Mark A.; Norton, Monica B.; Reinhard, Emily J.; Olins, Gillian M.; Corpus, Valerie M.; Palomo, Maria A.; McGraw, Dean E.; McMahon, Ellen G.

doi:10.1016/s0960-894x(01)81130-6

Cited by 6 publications

(3 citation statements)

References 4 publications

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“…Shortening the chain length to ethyl or trifluoroethyl and introducing a phenyl group resulted in a substantial decrease in potency. Thus, interchanging the N 1 −C 2 atoms of imidazoles such as II maintains in vitro potency, a result which contrasts with the observed in a related series of triazoles, where such a change provides a substantial decrease in potency.…”

Section: Resultsmentioning

confidence: 71%

Synthesis and Structure−Activity Relationship of a New Series of Potent AT₁ Selective Angiotensin II Receptor Antagonists: 5-(Biphenyl-4-ylmethyl)pyrazoles

Almansa

et al. 1997

J. Med. Chem.

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The synthesis and pharmacological activity of a new series of 5-(biphenyl-4-ylmethyl)pyrazoles as potent angiotensin II antagonists both in vitro (binding of [3H]AII) and in vivo (iv, inhibition of AII-induced increase in blood pressure, pithed rats; po, furosemide-treated sodium-depleted rats) are reported. The various substituents of the pyrazole ring have been modified taking into account the receptor's requirements derived from related structure−activity relationship studies. A propyl or butyl group at position 1 as well as a carboxylic acid group at position 4 were shown to be essential for high affinity. Different groups at position 3 (H, small alkyl, phenyl, benzyl) provided good binding affinity, but oral activity was highly discriminating: bulky alkyl groups provided the highest potencies. Among the acidic isosteres tested in the biphenyl moiety, the tetrazole group proved to be the best. Compound 14n (3-tert-butyl-1-propyl-5-[[2‘-(1H-tetrazol-5-yl)-1,1‘-biphenyl-4-yl]methyl]-1H-pyrazole-4-carboxylic acid, UR-7280) shows high potency both in vitro (IC50 = 3 nM) and in vivo (iv, 61.2 ± 10% decrease in blood pressure at 0.3 mg/kg; po, 30 mmHg fall in blood pressure at 0.3 mg/kg), in comparison to losartan (IC50 = 59 nM; iv, 62.5 ± 8.9% decrease in blood pressure at 1 mg/kg; po, 13 mmHg fall in blood pressure at 3 mg/kg). These data, together with the good pharmacokinetic profile of 14n in different species, have led to its selection for clinical evaluation as an antihypertensive agent.

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Section: Resultsmentioning

confidence: 71%

Synthesis and Structure−Activity Relationship of a New Series of Potent AT₁ Selective Angiotensin II Receptor Antagonists: 5-(Biphenyl-4-ylmethyl)pyrazoles

Almansa

et al. 1997

J. Med. Chem.

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Section: Discussionmentioning

confidence: 99%

“…It is known that triazole compounds have very important biological properties such as antimicrobial, antitumor, antioxidant, an enzyme inhibitor, antidepressant, antituberculous, anti-inflammatory and antihypertensive. [23][24][25][26][27][28][29] Triazole compounds are widely used in biochemistry, organic chemistry, and pharmaceutical chemistry due to their extensive pharmacological properties.…”

Section: Malignant Tumoral Lesionmentioning

confidence: 99%

In vitro and histological investigation of antitumor effect of some triazole compounds in colon cancer cell line

Parlak

Tekin

Karatepe

et al. 2019

J of Cellular Biochemistry

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1,2,4-Triazoles are used as antifungal, antibacterial, antimicrobial, and antioxidant against some oxidative radical species. Recently, many 1,2,4triazoles continue to be synthesized. In this study, the effect of the 1,2,4-triazole derivatives on human colon cancer (HT29) was investigated in vitro and in vivo in rats. MTT test was applied to in in vitro experiments. For in vivo study, rats were divided into seven groups as follows: Control group (negative control), azoxymethane (AOM), AOM + cisplatin 15, AOM + L1, AOM + L2, AOM + L3, and AOM + L4. To create colon cancer, the AOM injection was injected subcutaneously at a dose of 15 mg/kg, three times (once weekly). The in vivo studies were completed at 28 weeks. It was found that the 1,2,4-triazole derivatives reduced the cell viability (P < 0.05). In all animals in the experimental groups, mild dysplasia was detected in 100% of the colon mucosal epithelium. Severe dysplasia and adenocarcinoma were observed in L1 groups. As a result, this study determined that the 1,2,4-triazole derivatives exhibit antitumor activity. K E Y W O R D Sazoxymethane, colon cancer, HT29, 1,2,4-triazole | INTRODUCTIONIn the United States, colorectal cancer (CRC) is the second leading cause of cancer-related deaths. 1 In United States, 135 430 people were diagnosed with CRC and about 50 260 died from CRC in 2017. 2 CRC is the third most commonly diagnosed cancer and the third leading cause of cancer-specific mortality in both men and women. As of 2017, 95 520 new colon cancer cases (colon cancer alone) and 50 260 deaths (colon and rectum cancers in combination) are estimated to occur in the United States. With the increase in the access to and use

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ChemInform Abstract: 1H‐1,2,4‐Triazole Angiotensin II Receptor Antagonists: “C‐Linked” Analogues of SC‐50560.

et al. 1994

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1H-1,2,4-Triazole Angiotensin II Receptor Antagonists: "C-Linked" Analogues of SC-50560.-Biaryl (VI) shows nearly identical pharmacological effects in rats as its known N-linked analogue. -(REITZ, D. B.; PENICK, M. A.; NORTON, M. B.; REINHARD, E. J.; OLINS, G. M.; CORPUS, V. M.; PALOMO, M. A.; MCGRAW, D. E.; MCMAHON, E. G.; Bioorg. Med. Chem. Lett. 4 (1994) 1, 105-110; Searle Res. Dev., Monsanto Co., St. Louis, MO 63198, USA; EN)

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1H-1,2,4-triazole angiostensin II receptor antagonists: “qC-linked”q analogs of SC-50560

Cited by 6 publications

References 4 publications

Synthesis and Structure−Activity Relationship of a New Series of Potent AT₁ Selective Angiotensin II Receptor Antagonists: 5-(Biphenyl-4-ylmethyl)pyrazoles

Synthesis and Structure−Activity Relationship of a New Series of Potent AT₁ Selective Angiotensin II Receptor Antagonists: 5-(Biphenyl-4-ylmethyl)pyrazoles

In vitro and histological investigation of antitumor effect of some triazole compounds in colon cancer cell line

ChemInform Abstract: 1H‐1,2,4‐Triazole Angiotensin II Receptor Antagonists: “C‐Linked” Analogues of SC‐50560.

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1H-1,2,4-triazole angiostensin II receptor antagonists: “qC-linked”q analogs of SC-50560

Cited by 6 publications

References 4 publications

Synthesis and Structure−Activity Relationship of a New Series of Potent AT1 Selective Angiotensin II Receptor Antagonists: 5-(Biphenyl-4-ylmethyl)pyrazoles

Synthesis and Structure−Activity Relationship of a New Series of Potent AT1 Selective Angiotensin II Receptor Antagonists: 5-(Biphenyl-4-ylmethyl)pyrazoles

In vitro and histological investigation of antitumor effect of some triazole compounds in colon cancer cell line

ChemInform Abstract: 1H‐1,2,4‐Triazole Angiotensin II Receptor Antagonists: “C‐Linked” Analogues of SC‐50560.

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Synthesis and Structure−Activity Relationship of a New Series of Potent AT₁ Selective Angiotensin II Receptor Antagonists: 5-(Biphenyl-4-ylmethyl)pyrazoles

Synthesis and Structure−Activity Relationship of a New Series of Potent AT₁ Selective Angiotensin II Receptor Antagonists: 5-(Biphenyl-4-ylmethyl)pyrazoles