Potent, selective 3-pyridylethanolamine β3 adrenergic receptor agonists possessing a thiazole benzenesulfonamide pharmacophore

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Abstract

A series of thiazole benzenesulfonamide-substituted 3-pyridylethanolamines was prepared and evaluated for their human β3 adrenergic receptor agonist activity. Incorporation of aryl and heteroaryl substitution in the 4-position of the thiazole ring resulted in a number of highly potent and selective β3 agonists. Results of preliminary in vivo evaluation of several of these compounds is described.

Section snippets

Chemistry

The synthetic route used to prepare the thiazole sulfonamides Figure 2, Scheme 1 is outlined in Scheme 1. Coupling of aniline 69 with 4-cyanobenzenesulfonyl chloride, followed by treatment with hydrogen sulfide and triethylamine, afforded the intermediate thioamide 7. Condensation of 7 with the requisite α-chloroketones, followed by TFA removal of the BOC protecting group, afforded the thiazole sulfonamides Figure 2, Scheme 1.

Additionally, two compounds in the homologous series 8 were prepared

Pharmacology

Compounds 5au, 8a and 8f were tested in vitro for their ability to stimulate increases in cAMP in Chinese hamster ovary (CHO) cells expressing the cloned human β3 receptor. The activity of an agonist at the β3 AR is best described by its ability to stimulate adenylyl cyclase in a functional assay, since this method measures the affinity of a compound for the high-affinity, G-protein coupled state of the receptor. As a result, this assay accurately predicts the lipolytic potential of compounds

Acknowledgements

We thank Mr. Paul Cunningham and Mr. Donald Hora, Jr. for assistance with the in vivo experiments, Ms. Amy Bernick for mass spectral analyses, Mr. Joe Leone for preparation of intermediate 6, and Professor James G. Granneman (Wayne State University) for supplying the cloned human β3 receptor.

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