2. Academic Validation
  3. 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

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

Affiliation

  • 1 Chemistry Research Laboratories, Astellas Pharma Inc, Tsukuba-shi, Ibaraki 305-8585, Japan. kouji.hattori@jp.astellas.com
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.

Figures