Biarylaniline phenethanolamines as potent and selective beta3 adrenergic receptor agonists

Journal of Medicinal Chemistry
David E UehlingConrad Cowan

Abstract

The synthesis of a series of phenethanolamine aniline agonists that contain an aniline ring on the right-hand side of the molecule substituted at the meta position with a benzoic acid or a pyridyl carboxylate is described. Several of the analogues (e.g., 34, 36-38, 40, and 44) have high beta(3) adrenergic receptor (AR) potency and selectivity against beta(1) and beta(2) ARs in Chinese hamster ovary (CHO) cells expressing beta ARs. The dog pharmacokinetic profile of some of these analogues showed >25% oral bioavailability and po half-lives of at least 1.5 h. Among the compounds described herein, the 3,3'-biarylaniline carboxylate derivatives 36, 38 and the phenylpyridyl derivative 44 demonstrated outstanding in vitro properties and reasonable dog pharmacokinetic profiles. These three analogues also showed dose dependent beta(3) AR mediated responses in mice. The ease of synthesis and superior dog pharmacokinetics of compound 38 relative to that of 44 in combination with its in vitro profile led us to choose this compound as a development candidate for the treatment of type 2 diabetes.

References

Sep 8, 1989·Science·L J EmorineA D Strosberg
Oct 1, 1996·Trends in Pharmacological Sciences·A D Strosberg, F Pietri-Rouxel
Oct 20, 1998·Acta Physiologica Scandinavica·Y IgawaO Nishizawa
Jun 18, 1999·Cardiovascular Drugs and Therapy·C Smith, M Teitler
Jun 4, 2002·Current Drug Targets·M H Moneva, S Dagogo-Jack
Oct 4, 2002·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Rajkumar SevakDevdas Santani

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Citations

Dec 25, 2012·Naunyn-Schmiedeberg's Archives of Pharmacology·Yasuhiko Igawa, Martin C Michel
May 4, 2011·Journal of Chemical Information and Modeling·Kuldeep K Roy, Anil K Saxena
Jan 6, 2015·Expert Opinion on Investigational Drugs·Pamela Ellsworth, Jennifer Fantasia
Jan 19, 2010·Angewandte Chemie·Masayuki WasaJin-Quan Yu
Mar 29, 2008·American Journal of Physiology. Gastrointestinal and Liver Physiology·April B M GrudellAlan R Zinsmeister
Mar 15, 2019·British Journal of Pharmacology·Yasuhiko IgawaMartin C Michel
Mar 2, 2021·Frontiers in Pharmacology·Gabriela Reolon PassosFabiola Zakia Mónica
Dec 18, 2007·Bioorganic & Medicinal Chemistry·Maria Grazia PerroneAntonio Scilimati

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