Quality by design (QbD) of amide isosteres: 5,5-Disubstituted isoxazolines as potent CRTh2 antagonists with favorable pharmacokinetic and drug-like properties

Bioorg Med Chem Lett. 2014 Mar 15;24(6):1615-20. doi: 10.1016/j.bmcl.2014.01.043. Epub 2014 Feb 2.

Abstract

Isoxazoles are frequently used amide isosteres, as shown in the context of discovery of CRTh2 antagonists from amide 1 to isoxazole 2. However, persistent agonism and poor solubility in isoxazole series presented challenges to its further development. Based on the concept of quality by design (QbD), 5,5-disubstituted isoxazolines 3 were introduced. The chirality at 5 position of isoxazolines controlled the switch between two modes of actions, which led to a novel series of pure antagonists. This non-planar motif also conferred a change of shape of these molecules, which avoided flat structures and improved their physical properties.

Keywords: Agonism/antagonism switch; Amide isostere; CRTh(2) antagonists; Drug-like properties; Isoxazolines; Quality by design (QbD).

MeSH terms

  • Amides / chemistry*
  • Animals
  • Dogs
  • Drug Design*
  • Half-Life
  • Haplorhini
  • Humans
  • Isoxazoles / chemical synthesis
  • Isoxazoles / chemistry*
  • Isoxazoles / pharmacokinetics
  • Quinazolinones / chemical synthesis
  • Quinazolinones / chemistry*
  • Quinazolinones / pharmacokinetics
  • Rats
  • Rats, Wistar
  • Receptors, Immunologic / antagonists & inhibitors*
  • Receptors, Immunologic / metabolism
  • Receptors, Prostaglandin / antagonists & inhibitors*
  • Receptors, Prostaglandin / metabolism
  • Solubility
  • Structure-Activity Relationship

Substances

  • Amides
  • Isoxazoles
  • Quinazolinones
  • Receptors, Immunologic
  • Receptors, Prostaglandin
  • prostaglandin D2 receptor