Synthesis, modification, and evaluation of (R)-de-O-methyllasiodiplodin and analogs as nonsteroidal antagonists of mineralocorticoid receptor

Bioorg Med Chem Lett. 2011 Feb 15;21(4):1171-5. doi: 10.1016/j.bmcl.2010.12.101. Epub 2010 Dec 25.

Abstract

Macrolide (R)-de-O-methyllasiodiplodin (1), discovered to be a potent nonsteroidal antagonist of the mineralocorticoid receptor (MR), was synthesized via an efficient method and evaluated for MR antagonistic activity together with its analogs. Among all the tested compounds, compounds 18a, 18b and 18c, exhibited more potent antagonistic activity against MR with IC(50) values ranging from 0.58 to 1.11 μM. Generally, it was obviously demonstrated that acetylation at phenolic hydroxyl groups and the ring size in analogs of 1 were very important for MR antagonist activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Estrogen Receptor alpha / antagonists & inhibitors
  • Estrogen Receptor alpha / metabolism
  • Macrolides / chemical synthesis*
  • Macrolides / chemistry
  • Macrolides / pharmacology
  • Mineralocorticoid Receptor Antagonists*
  • Receptors, Glucocorticoid / antagonists & inhibitors
  • Receptors, Glucocorticoid / metabolism
  • Receptors, Mineralocorticoid / metabolism
  • Receptors, Progesterone / antagonists & inhibitors
  • Receptors, Progesterone / metabolism
  • Structure-Activity Relationship
  • Two-Hybrid System Techniques

Substances

  • Estrogen Receptor alpha
  • Macrolides
  • Mineralocorticoid Receptor Antagonists
  • Receptors, Glucocorticoid
  • Receptors, Mineralocorticoid
  • Receptors, Progesterone
  • de-O-methyllasiodiplodin