Identification of Potent and Selective Inhibitors of PDGF Receptor Autophosphorylation

Abstract

We report the structure-activity relationship of quinoline and quinazoline derivatives, which include urea, thiourea, urethane, and acylthiourea groups, as inhibitors of the platelet-derived growth factor (PDGF) receptor autophosphorylation. Our previous studies showed that the quinoline and quinazoline derivatives including urea, thiourea, and carbamate groups were highly potent compounds as the PDGF receptor autophosphorylation inhibitor, but these compounds did not exhibit receptor selectivity between the PDGF receptor and the c-kit receptor. As a result of further synthesis and biological evaluation, we have found that the quinoline and quinazoline-acylthiourea derivatives showed not only good inhibitory activity for the PDGF receptor but also receptor selectivity between the PDGF receptor and the c-kit receptor. Furthermore N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(2-methylbenzoyl)thiourea exhibited potent oral efficacy in in vivo assay using the rat carotid balloon injury model. Therefore, the quinoline and quinazoline-acylthiourea derivatives may be expected to have potential as therapeutic agents for the treatment of restenosis.

Platelet-Derived Growth Factor Receptor Activation Promotes the Prodestructive Invadosome-Forming Phenotype of Synoviocytes from Patients with Rheumatoid Arthritis

“…4A). We then blocked either PDGFR activity using PDGFR tyrosine kinase inhibitor V, which inhibits ligand-induced PDGFR phosphorylation and kinase activity (45), or endogenous PDGFR ligands using PDGF-B and pan-PDGF neutralizing Abs. Results showed that invadosome formation induced by PDGF-B in control synovial cells or already elevated in RA cells was abolished by the addition of PDGF neutralizing Abs or PDGFR tyrosine kinase inhibitor V (Fig.…”

Synthesis and phytotoxic activity of novel acylthiourea and 2H-1,2,4-thiadiazolo[2,3-.ALPHA.]pyrimidine derivatives

“…By analyzing the relationship between molecular structure and activity, it was found that the compound, in which both R 1 and R 2 are OCH 3 or CH 3 , or one is OCH 3 and the other is CH 3 , possesses relatively high phytotoxic activity.…”

“…Heterocyclic acylthioureas exhibit excellent biological activities, such as fungicidal, 1) insecticidal, 2) antitumor 3) and regulation of plant growth, 4) and some acylthioureas containing 4,6-disubstitued pyrimidinyl possess herbicidal activity. 5) Additionally, N-4,6-disubstitued pyrimidinyl acylthiourea can be transformed into fused heterocyclic derivative (e.g.…”

Quinazoline-urea, new protein kinase inhibitors in treatment of prostate cancer

“…Treatment of quinazolinone 5 in refluxing phosphorus oxychloride afforded the chloroquinazoline derivative in good yield (>90%). In series B, compound 10 was prepared according to procedures previously described by Furuta et al 41 using methyl 2-amino-4,5-dimethoxybenzoate 8 as starting material. To prepare series C, the same synthesis route was employed as for series A.…”