2-(Anilinomethyl)imidazolines as α1 Adrenergic Receptor Agonists:  the Discovery of α1a Subtype Selective 2‘-Alkylsulfonyl-Substituted Analogues

Hodson, Stephen J.; Bishop, Michael J.; Speake, Jason D.; Navas, Frank; Garrison, Deanna T.; Bigham, Eric C.; Saussy, David L.; Liacos, J. A.; Irving, Paul E.; Gobel, Michael J; Sherman, Bryan W.

doi:10.1021/jm000542r

Cited by 27 publications

(6 citation statements)

References 19 publications

(20 reference statements)

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“…Starting Materials . Aniline and 4-(trifluoromethyl)-, 4-chloro-, 4-methoxy-, 4-(methylsulfanyl)-, 4-acetyl-, 2-(methylsulfanyl)-, and 2-iodoaniline were commercially available; 4-azidoaniline, 4-chloro-2-(methylsulfanyl)aniline, 5-chloro-2-(methylsulfanyl)aniline, and 2-(2-phenylethynyl)aniline were synthesized according to the literature. The corresponding diazonium tetrafluoroborates 7a − g were prepared following usual procedures…”

Section: Methodsmentioning

confidence: 99%

Cascade Radical Reactions via α-(Arylsulfanyl)imidoyl Radicals: Competitive [4 + 2] and [4 + 1] Radical Annulations of Alkynyl Isothiocyanates with Aryl Radicals

et al. 2003

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Aryl radicals react with 2-(2-phenylethynyl)phenyl isothiocyanate through a novel radical cascade reaction entailing formation of alpha-(arylsulfanyl)imidoyl radicals and affording a new class of compounds, i.e. thiochromeno[2,3-b]indoles. These derivatives are formed as mixtures of substituted analogues arising from competitive [4 + 2] and [4 + 1] radical annulations. The isomer ratio is strongly dependent on the aryl substituent and is correlated to its capability to delocalize spin density. The presence of a methylsulfanyl group in the ortho-position of the initial aryl radical results in complete regioselectivity and better yields, as the consequence of both strong spin-delocalization effect, which promotes exclusive [4 + 1] annulation, and good radical leaving-group ability, which facilitates aromatization of the final cyclohexadienyl radical. Theoretical calculations support the hypothesis of competitive, independent [4 + 2] and [4 + 1] annulation pathways. They also suggest that rearrangement onto the sulfur atom of the [4 + 1] intermediate does not occur via a sulfuranyl radical but rather through either a transition state or a sulfur-centered (thioamidyl) radical; the latter is possibly the preferred route in the presence of an o-methylsulfanyl moiety that can act as a leaving group in the final ipso-cyclization process.

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Section: Methodsmentioning

confidence: 99%

Cascade Radical Reactions via α-(Arylsulfanyl)imidoyl Radicals: Competitive [4 + 2] and [4 + 1] Radical Annulations of Alkynyl Isothiocyanates with Aryl Radicals

et al. 2003

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“…(10)) [56][57][58][59][60][61][62]. The best compounds generally derive their selectivity from key substituents at the 2-position on the aromatic ring.…”

Section: α 1a Selective Agonistsmentioning

confidence: 99%

Recent Advances in the Discovery of α1-Adrenoceptor Agonists

Bishop¹

2007

CTMC

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The alpha(1) adrenoceptors are three of nine well-characterized receptors that are activated by epinephrine and norepinephrine. Agonists acting at the alpha(1) adrenoceptors produce numerous physiological effects, and are used therapeutically for several indications. Many known alpha(1) adrenoceptor agonists are alpha(1A) selective, but the discovery of highly selective alpha(1B) and alpha(1D) adrenoceptor agonists has proven to be an extremely difficult goal to achieve. This review will focus on recent advances in the discovery, development and clinical utility of subtype-specific alpha(1) agonists as well as contributions to our understanding of agonist-receptor interactions.

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“…The -NH-CH 2 -bridge also demonstrated to be compatible with α 1 -AR agonist activity, with compound 9 showing high selectivity for α 1a -AR over α 1b -e α 1d -AR (250 and 7000 fold, respectively) [16].…”

mentioning

confidence: 92%

The 2-substituted imidazoline ring linked to an aromatic moiety by a biatomic bridge: a bioversatile scaffold

Bello¹,

Giannella²,

Piergentili³

et al. 2016

Glob Drugs Therap

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2-(Anilinomethyl)imidazolines as α₁ Adrenergic Receptor Agonists: the Discovery of α₁_a Subtype Selective 2‘-Alkylsulfonyl-Substituted Analogues

Cited by 27 publications

References 19 publications

Cascade Radical Reactions via α-(Arylsulfanyl)imidoyl Radicals: Competitive [4 + 2] and [4 + 1] Radical Annulations of Alkynyl Isothiocyanates with Aryl Radicals

Cascade Radical Reactions via α-(Arylsulfanyl)imidoyl Radicals: Competitive [4 + 2] and [4 + 1] Radical Annulations of Alkynyl Isothiocyanates with Aryl Radicals

Recent Advances in the Discovery of α1-Adrenoceptor Agonists

The 2-substituted imidazoline ring linked to an aromatic moiety by a biatomic bridge: a bioversatile scaffold

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2-(Anilinomethyl)imidazolines as α1 Adrenergic Receptor Agonists: the Discovery of α1a Subtype Selective 2‘-Alkylsulfonyl-Substituted Analogues

Cited by 27 publications

References 19 publications

Cascade Radical Reactions via α-(Arylsulfanyl)imidoyl Radicals: Competitive [4 + 2] and [4 + 1] Radical Annulations of Alkynyl Isothiocyanates with Aryl Radicals

Cascade Radical Reactions via α-(Arylsulfanyl)imidoyl Radicals: Competitive [4 + 2] and [4 + 1] Radical Annulations of Alkynyl Isothiocyanates with Aryl Radicals

Recent Advances in the Discovery of &#945;1-Adrenoceptor Agonists

The 2-substituted imidazoline ring linked to an aromatic moiety by a biatomic bridge: a bioversatile scaffold

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Product

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2-(Anilinomethyl)imidazolines as α₁ Adrenergic Receptor Agonists: the Discovery of α₁_a Subtype Selective 2‘-Alkylsulfonyl-Substituted Analogues

Recent Advances in the Discovery of α1-Adrenoceptor Agonists