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1.
Cancer Res ; 60(4): 970-5, 2000 Feb 15.
Article in English | MEDLINE | ID: mdl-10706112

ABSTRACT

There is evidence that vascular endothelial growth factor (VEGF) contributes to solid tumor growth through the promotion of both angiogenesis and tumor vascular permeability. To abrogate VEGF signaling, we developed a small molecular weight inhibitor of VEGF receptor tyrosine kinase (RTK) activity that was compatible with chronic oral administration. ZD4190, a substituted 4-anilinoquinazoline, is a potent inhibitor of KDR and Flt-1 RTK activity, and VEGF stimulated HUVEC proliferation in vitro. Chronic once-daily oral dosing of ZD4190 to young rats produced a dose-dependent increase in the femoral epiphyseal growth plate area, which may be attributed to the inhibition of VEGF signaling in vivo because vascular invasion of cartilage is a prerequisite to the process of ossification. Once-daily oral dosing of ZD4190 to mice bearing established (approximately 0.5 cm3) human tumor xenografts (breast, lung, prostate, and ovarian) elicited significant antitumor activity and at doses that would not be expected to have any direct antiproliferative effect on tumor cells. Prolonged tumor cytostasis was further demonstrated in a PC-3 xenograft model with 10 weeks of ZD4190 dosing, and upon withdrawal of therapy, tumor growth resumed after a short delay. These observations are entirely consistent with the proposed mode of action. ZD4190 is one of a series of VEGF RTK inhibitors that may have utility in the treatment of a range of histologically diverse solid tumor types.


Subject(s)
Antineoplastic Agents/pharmacology , Quinazolines/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptors, Growth Factor/antagonists & inhibitors , Triazoles/pharmacology , Administration, Oral , Animals , Epiphyses/drug effects , Epiphyses/pathology , Female , Humans , Hypertrophy , Mice , Neoplasm Transplantation , Rats , Receptors, Vascular Endothelial Growth Factor , Transplantation, Heterologous , Tumor Cells, Cultured
2.
J Med Chem ; 43(26): 4964-72, 2000 Dec 28.
Article in English | MEDLINE | ID: mdl-11150166

ABSTRACT

A novel series of 4-piperidinopyridines and 4-piperidinopyrimidines showed potent and selective inhibition of rat 2,3-oxidosqualene cyclase-lanosterol synthase (OSC) (e.g. 26 IC(50) rat = 398 +/- 25 nM, human = 112 +/- 25 nM) and gave selective oral inhibition of rat cholesterol biosynthesis (26 ED(80) = 1.2 +/- 0.3 mg/kg, n = 5; HMGCoA reductase inhibitor simvastatin ED(80) = 1.2 +/- 0.3 mg/kg, n = 5). The piperidinopyrimidine OSC inhibitors have a significantly lower pK(a) than the corresponding pyridine or the previously reported quinuclidine OSC inhibitor series. This indicates that other novel OSC inhibitors may be found in analogues of this series across a broader pK(a) range (6.0-9.0). These series may yield novel hypocholesterolemic agents for the treatment of cardiovascular disease.


Subject(s)
Anticholesteremic Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Intramolecular Transferases/antagonists & inhibitors , Piperazines/chemical synthesis , Piperidines/chemical synthesis , Pyridines/chemical synthesis , Pyrimidines/chemical synthesis , Administration, Oral , Animals , Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacology , Cholesterol/biosynthesis , Chromatography, High Pressure Liquid , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , In Vitro Techniques , Microsomes/drug effects , Microsomes/enzymology , Piperazines/chemistry , Piperazines/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Structure-Activity Relationship
3.
J Med Chem ; 42(7): 1306-11, 1999 Apr 08.
Article in English | MEDLINE | ID: mdl-10197973

ABSTRACT

Novel 3-substituted quinuclidine inhibitors of cholesterol biosynthesis are reported. Compounds were optimized against oxidosqualene cyclase-lanosterol synthase (OSC) inhibition in vivo, rather than by the conventional optimization of structure-activity relationship information based on in vitro OSC inhibition. Thus, examination of HPLC lipid profiles from orally dosed rats showed cholesterol biosynthetic intermediates and whether cholesterol levels were reduced. A new substituted quinuclidine pharmacophore 18a-c was rapidly found for the inhibition of OSC, and the most promising inhibitors were validated by the confirmation of potent OSC inhibition. Compound 16 gave an IC50 value of 83 +/- 11 nM for human and an IC50 value of 124 +/- 14 nM, for rat, coupled with oral and selective inhibition of cholesterol biosynthesis derived from OSC inhibition (rat, ED50 = 1.3 +/- 0.7 mg/kg, n = 5; marmoset, 15 mg/kg dose, n = 3, caused complete inhibition). These 3-substituted quinuclidines, which were derived from a quinuclidine series previously known to inhibit cholesterol biosynthesis at the squalene synthase step, may afford a novel series of hypocholesterolemic agents acting by the inhibition of OSC.


Subject(s)
Anticholesteremic Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Intramolecular Transferases/antagonists & inhibitors , Lipid Metabolism , Quinuclidines/chemical synthesis , Administration, Oral , Animals , Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacology , Callithrix , Chromatography, High Pressure Liquid , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , In Vitro Techniques , Lipids/analysis , Liver/chemistry , Liver/drug effects , Male , Microsomes/drug effects , Microsomes/metabolism , Quinuclidines/chemistry , Quinuclidines/pharmacology , Rats , Structure-Activity Relationship
4.
J Med Chem ; 42(26): 5369-89, 1999 Dec 30.
Article in English | MEDLINE | ID: mdl-10639280

ABSTRACT

A series of substituted 4-anilinoquinazolines and related compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptor (Flt and KDR) tyrosine kinase activity. Enzyme screening indicated that a narrow structure-activity relationship (SAR) existed for the bicyclic ring system, with quinazolines, quinolines, and cinnolines having activity and with quinazolines and quinolines generally being preferred. Substitution of the aniline was investigated and clearly indicated that small lipophilic substituents such as halogens or methyl were preferred at the C-4' position. Small substituents such as hydrogen and fluorine are preferred at the C-2' position. Introduction of a hydroxyl group at the meta position of the aniline produced the most potent inhibitors of Flt and KDR tyrosine kinases activity with IC(50) values in the nanomolar range (e.g. 10, 12, 13, 16, and 18). Investigation of the quinazoline C-6 and C-7 positions indicates that a large range of substituents are tolerated at C-7, whereas variation at the C-6 is more restricted. At C-7, neutral, basic, and heteroaromatic side chains led to very potent compounds, as illustrated by the methoxyethoxy derivative 13 (IC(50) < 2 nM). Our inhibitors proved to be very selective inhibitors of Flt and KDR tyrosine kinase activity when compared to that associated with the FGF receptor (50- to 3800-fold). Observed enzyme profiles translated well with respect to potency and selectivity for inhibition of growth factor stimulated proliferation of human umbilical vein endothelial cells (HUVECs). Oral administration of selected compounds to mice produced total plasma levels 6 h after dosing of between 3 and 49 microM. In vivo efficacy was demonstrated in a rat uterine oedema assay where significant activity was achieved at 60 mg/kg with the meta hydroxy anilinoquinazoline 10. Inhibition of growth of human tumors in athymic mice has also been demonstrated: compound 34 inhibited the growth of established Calu-6 lung carcinoma xenograft by 75% (P < 0.001, one tailed t-test) following daily oral administration of 100 mg/kg for 21 days.


Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptors, Growth Factor/antagonists & inhibitors , Animals , Biological Availability , Cell Division/drug effects , Cells, Cultured , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Enzyme Inhibitors/blood , Female , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Mice, Nude , Models, Molecular , Neoplasm Transplantation , Organ Size , Quinazolines/blood , Rats , Receptors, Vascular Endothelial Growth Factor , Structure-Activity Relationship , Tumor Cells, Cultured , Uterus/drug effects
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