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.
Subject(s)
Adrenergic Agonists/chemistry , Adrenergic beta-3 Receptor Agonists , Receptors, Adrenergic, beta-2/chemistry , Sulfonamides/chemistry , Adrenergic Agonists/chemical synthesis , Adrenergic Agonists/pharmacokinetics , Animals , Binding Sites , Computer Simulation , Crystallography, X-Ray , Dogs , Drug Discovery , Humans , Models, Chemical , Receptors, Adrenergic, beta-3/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokineticsABSTRACT
Sordarin is a unique natural product antifungal agent that is an inhibitor of elongation factor 2. To improve biological activity, we synthesized various compounds by novel modification of the aglycone, sordaricin. As a result, we have discovered the novel sordarin derivative FR290581. This compound exhibited superior activity and a good pharmacokinetic profile, and also displayed good in vivo activity against Candida albicans.
