Identification of 4-piperazin-1-yl-quinazoline template based aryl and benzyl thioureas as potent, selective, and orally bioavailable inhibitors of platelet-derived growth factor (PDGF) receptor

Bioorg Med Chem Lett. 2004 Oct 4;14(19):4867-72. doi: 10.1016/j.bmcl.2004.07.041.

Abstract

4-[4-(N-Substituted-thio-carbamoyl)-1-piperazinyl]-6-methoxy-7-alkoxyamino-quinazoline derivatives such as 14 (CT53986) have been identified to be potent and selective inhibitors of the phosphorylation of PDGFR. SAR-investigations are described in the arylamine segment, C-7 appendage, and the thiourea moiety. Bioisosteres of thiourea (cyanoguanidine), and of quinazoline (quinoline-3-carbonitrile) were synthesized and are compared for their in vitro inhibitory activity. PK profiles of the optimized compounds in rat, dog, and cynomolgus monkey are described.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Dogs
  • Macaca fascicularis
  • Quinazolines / chemical synthesis
  • Quinazolines / pharmacology
  • Rats
  • Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Thiourea / chemical synthesis*
  • Thiourea / pharmacology

Substances

  • Quinazolines
  • Receptors, Platelet-Derived Growth Factor
  • Thiourea