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Identification of orally active, potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family.

Abstract：

:We have previously found that the 4-[4-(N-substituted carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazolines can function as potent and selective inhibitors of platelet-derived growth factor receptor (PDGFR) phosphorylation. A series of highly potent, specific, orally active, small molecule kinase inhibitors directed against members of PDGFR receptor have been developed through modifications of the novel quinazoline template I. Systematic modifications in the A-bicyclic ring and D-rings of protype I were carried out to afford potent analogues, which display IC(50) values of <250 nM in cellular betaPDGFR phosphorylation assays. An optimized analogue in this series, 75 (CT53518), inhibits Flt-3, betaPDGFR, and c-Kit receptor phosphorylation with IC(50) values of 50-200 nM, whereas 15-20-fold less potent activity against CSF-1R was observed. This analogue also inhibits autophosphorylation of Flt-3 ligand-stimulated wild-type Flt-3 and a constitutively activated Flt-3/internal tandem duplication (ITD) with IC(50) values of 30-100 nM. Through this optimization process, 75 was found to be metabolically stable and has desirable pharmacokinetic properties in all animal species studied (F% > 50%, T(1/2) > 8 h). Oral administration of 75 promotes mice survival and significantly delayed disease progression in a Flt-3/ITD-mediated leukemia mouse model and shows efficacy in a nude mouse model of chronic myelomonocytic leukemia.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Pandey A,Volkots DL,Seroogy JM,Rose JW,Yu JC,Lambing JL,Hutchaleelaha A,Hollenbach SJ,Abe K,Giese NA,Scarborough RM

doi

10.1021/jm020143r

keywords:

subject

Has Abstract

pub_date

2002-08-15 00:00:00

pages

3772-93

issue

17

eissn

0022-2623

issn

1520-4804

pii

jm020143r

journal_volume

45

pub_type

杂志文章

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