α1-Adrenoceptor Agonists: The Identification of Novel α1A Subtype Selective 2′-Heteroaryl-2-(phenoxymethyl)imidazolines

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Abstract

Novel 2′-heteroaryl-2-(phenoxymethyl)imidazolines have been identified as potent agonists of the cloned human α1-adrenoceptors in vitro. The nature of the 2′-heteroaryl group can have significant effects on the potency, efficacy, and subtype selectivity in this series. α1A Subtype selective agonists have been identified.

Novel 2′-heteroaryl-2-(phenoxymethyl)imidazolines have been identified as potent agonists of the human α1-adrenoreceptors in vitro. α1A Subtype selective agonists have been identified.

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Chemistry11

A large number of 2′-heteroaryl-2-(phenoxymethyl)imidazolines were prepared and evaluated for agonist activity at the α1-adrenoceptor subtypes. A representative set of 2′-heteroaryl-2-(phenoxymethyl)imidazolines was selected to illustrate the SAR in this series (Fig. 4).

All of these analogues of compound 5 were prepared using a two-step approach from phenols using chloroacetonitrile followed by heating in neat ethylenediamine (Scheme 1).12

The 2-(heteroaryl)phenols used in the syntheses of

Results

To model the potential ability of ligands to activate the individual α1 subtypes in humans, all compounds were evaluated in a cell-based functional assay using the cloned human receptors expressed in rat-1 fibroblasts.20 The agonist potency (expressed as the pEC50) and efficacy (expressed as a percent of the maximal effect of the α1-adrenoceptor agonist standard, phenylephrine) of selected 2′-heteroaryl-2-(phenoxymethyl)imidazolines are reported in Table 1.

2′-Phenyl-2-(phenoxymethyl)imidazoline

Conclusions

A number of novel α1 agonists have been identified in the 2′-heteroaryl-2-(phenoxymethyl)imidazoline series, including some compounds with sub-nanomolar agonist potencies at the cloned human α1A-adrenoceptor (19 and 20). Several compounds in the series displayed agonist subtype selectivity for the cloned human α1A-adrenoceptor, with compounds 7, 25, 26, 27, 29 and 30 exhibiting greater than 1000-fold selectivity versus the cloned human α1B- and α1D-adrenoceptors in our functional agonism assay.

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