Identification of orally active, potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family.
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.
Pandey
Anjali
A
Medicinal Chemistry Department, In Vivo Sciences, Millennium Pharmaceuticals, Inc., 256 East Grand Avenue, South San Francisco, California 94080, USA. anjali_pandey@mpi.com
Volkots
Deborah L
DL
Seroogy
Joseph M
JM
Rose
Jack W
JW
Yu
Jin-Chen
JC
Lambing
Joseph L
JL
Hutchaleelaha
Athiwat
A
Hollenbach
Stanley J
SJ
Abe
Keith
K
Giese
Neill A
NA
Scarborough
Robert M
RM
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007942:Leukemia, Experimental / Q000188:drug therapy; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010949:Plasma; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3
D004791:Enzyme Inhibitors; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; C464670:tandutinib; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; C099852:PDGF receptor tyrosine kinase; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor; D051941:fms-Like Tyrosine Kinase 3