Discovery of highly potent and selective biphenylacylsulfonamide-based beta3-adrenergic receptor agonists and molecular modeling based on the solved X-ray structure of the beta2-adrenergic receptor: part 6

  • Bioorg Med Chem Lett. 2009 Aug 15;19(16):4679-83. doi: 10.1016/j.bmcl.2009.06.083.
Kouji Hattori  1 ,  Masaya Orita ,  Susumu Toda ,  Masashi Imanishi ,  Shinji Itou ,  Yutaka Nakajima ,  Daisuke Tanabe ,  Kenichi Washizuka ,  Takanobu Araki ,  Minoru Sakurai ,  Shigeo Matsui ,  Emiko Imamura ,  Koji Ueshima ,  Takao Yamamoto ,  Nobuhiro Yamamoto ,  Hirofumi Ishikawa ,  Keiko Nakano ,  Naoko Unami ,  Kaori Hamada ,  Yasuhiro Matsumura ,  Fujiko Takamura
Affiliations
  • 1. Chemistry Research Laboratories, Astellas Pharma Inc, Tsukuba-shi, Ibaraki 305-8585, Japan. [email protected]
PMID: 19608416 DOI: 10.1016/j.bmcl.2009.06.083
Abstract

As an extension of research, we have investigated modification of left-hand side (LHS) of biphenyl analogues containing an acylsulfonamide moiety in the development of potent and selective human beta(3)-adrenergic receptor (AR) agonists. Result of structure-activity relationships (SAR) and cassette-dosing evaluation in dogs showed that the hydroxynorephedrine analogue 16 had an excellent balance of in vitro and in vivo potency with pharmacokinetic profiles. In addition, to facilitate structure-based drug design (SBDD), we also have performed a docking study of biphenyl analogues based on the X-ray structure of the beta(2)-adrenergic receptor.