2,4-diamino-6,7-dimethoxyquinazolines. 1. 2-[4-(1,4-benzodioxan-2-ylcarbonyl)piperazin-1-yl] derivatives as alpha 1-adrenoceptor antagonists and antihypertensive agents.

doi:10.1021/JM00384A009

Paper

2,4-diamino-6,7-dimethoxyquinazolines. 1. 2-[4-(1,4-benzodioxan-2-ylcarbonyl)piperazin-1-yl] derivatives as alpha 1-adrenoceptor antagonists and antihypertensive agents.

Published 1987 · S. Campbell, M. Davey, J. D. Hardstone

Journal of medicinal chemistry

Q1 SJR score

103

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1

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Abstract

A series of 4-amino-2-[4-(1,4-benzodioxan-2-ylcarbonyl)piperazin-1 -yl]-6, 7-dimethoxyquinazoline derivatives was synthesized for evaluation as alpha-antagonists and antihypertensive agents. Most compounds displayed high (nM) binding affinity for alpha 1-adrenoceptors with no significant activity at alpha 2-sites. Selective antagonism of the alpha 1-mediated vasoconstrictor effects of norepinephrine is also characteristic of the series. Structure-activity relationships for alpha 1-adrenoceptor affinity are presented, and structural similarity between the 2,4-diamino-6,7-dimethoxyquinazoline nucleus and norepinephrine is established. An alpha 1-receptor model is presented in which charge-reinforced hydrogen bonding is important for binding of both antagonist and agonist molecules. Antihypertensive activity was evaluated after oral administration (5 mg/kg) to spontaneously hypertensive rats, and several compounds displayed similar efficacy to prazosin when assessed after 6 h. On the basis of alpha 1-adrenoceptor affinity/selectivity in vitro and duration of antihypertensive action in vivo, compound 1 (doxazosin) was selected for further evaluation and is currently progressing through phase III clinical trials.

Non-RCT

Animal Study

Highly Cited

Study Snapshot

Compound 1 (doxazosin) shows potential as an alpha 1-adrenoceptor antagonist and antihypertensive agent, with high binding affinity and selectivity for norepinephrine effects.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

2,4-diamino-6,7-dimethoxyquinazolines. 1. 2-[4-(1,4-benzodioxan-2-ylcarbonyl)piperazin-1-yl] derivatives as alpha 1-adrenoceptor antagonists and antihypertensive agents.

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References

Citations

Ru(II)-Catalyzed C-H Amination of 1,2,3-Benzotriazinones with Azide Compounds.

The Ru(II)-catalyzed C-H amination of 1,2,3-benzotriazinones with azide compounds effectively creates versatile heterocyclic amino products and phthalazinones, highlighting its synthetic practicability.

Synthesis and characterization of sulfonamide appended rigid phenyl-based and non-rigid 1,4-benzodioxan-based ring systems and their Pt(II) complexes towards potential therapeutic targets

The synthesized compounds show notable cytotoxic activity against non-small cell lung cancer cells, with the most pronounced effect being shown by [PtCl2(N(SO2 )(4-Mebip)dpa)]CH3 CN (C2).

2S-(1RS-benzyloxy-hex-5-enyl)-2,3-dihydro-1,4-benzodioxine

The precise configuration of 2S-(1R-benzyloxy-hex-5-enyl)-2,3-dihydro-1,4-benzodioxine and 2S-(1S-benzyloxy-hex-5-enyl)-2,3-di

The role of the methoxy group in approved drugs.

The methoxy group plays a crucial role in ligand-target binding, physicochemical properties, and ADME parameters in over 230 approved drugs, offering unique effects beyond the sum of individual parts.

Ru(II)‐Catalyzed Selective C—H Alkynylation of Isoquinolones, Quinazolones and Phthalazinones with Bromoalkynes

The new Ru(II)-catalyzed alkynylation reaction effectively synthesizes valuable alkynylated isoquinolone, quinazolone, and phthalazinone derivatives with wide substrate scope and high selectivity.