Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 29
Filter
Add more filters










Publication year range
1.
J Med Chem ; 44(17): 2719-34, 2001 Aug 16.
Article in English | MEDLINE | ID: mdl-11495584

ABSTRACT

A series of new 6-substituted-4-(3-bromophenylamino)quinazoline derivatives that may function as irreversible inhibitors of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases have been prepared. These inhibitors have, at the C-6 position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(3-bromophenylamino)quinazoline with unsaturated acid chlorides or mixed anhydrides. We show that attaching a basic functional group onto the Michael acceptor results in greater reactivity, due to intramolecular catalysis of the Michael addition and/or an inductive effect of the protonated basic group. This, along with improved water solubility, results in compounds with enhanced biological properties. We present molecular modeling and experimental evidence that these inhibitors interact covalently with the target enzymes. One compound, 16a, was shown to have excellent oral activity in a human epidermoid carcinoma (A431) xenograft model in nude mice.


Subject(s)
Antineoplastic Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , ErbB Receptors/antagonists & inhibitors , Quinazolines/chemical synthesis , Receptor, ErbB-2/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Blotting, Western , Cell Division/drug effects , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , Fluorometry , Glutathione/chemistry , Humans , Magnetic Resonance Spectroscopy , Mice , Mice, Nude , Models, Molecular , Phosphorylation , Precipitin Tests , Quinazolines/chemistry , Quinazolines/pharmacology , Transplantation, Heterologous , Tumor Cells, Cultured
2.
Bioorg Med Chem Lett ; 11(11): 1407-10, 2001 Jun 04.
Article in English | MEDLINE | ID: mdl-11378365

ABSTRACT

A series of 4-anilino-3-cyano-6,7-dialkoxyquinolines with different substituents attached to the 4-anilino group has been prepared that are potent MEK (MAP kinase kinase) inhibitors. The best activity is obtained when a phenyl or a thienyl group is attached to the para-position of the aniline through a hydrophobic linker, such as an oxygen, a sulfur, or a methylene group. The most active compounds show low nanomolar IC(50)'s against MEK (MAP kinase kinase), and have potent growth inhibitory activity in LoVo cells (human colon tumor line).


Subject(s)
Aniline Compounds/pharmacology , Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Quinolines/pharmacology , Aniline Compounds/chemistry , Antineoplastic Agents/chemistry , Cell Division/drug effects , Enzyme Inhibitors/chemistry , Humans , Quinolines/chemistry , Structure-Activity Relationship , Tumor Cells, Cultured
3.
J Med Chem ; 44(5): 822-33, 2001 Mar 01.
Article in English | MEDLINE | ID: mdl-11262092

ABSTRACT

Screening of a directed compound library in a yeast-based assay identified 4-[(2,4-dichlorophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile (2a) as a Src inhibitor. An enzymatic assay established that 2a was an ATP-competitive inhibitor of the kinase activity of Src. We present here SAR data for 2a which shows that the aniline group at C-4, the carbonitrile group at C-3, and the alkoxy groups at C-6 and C-7 of the quinoline are crucial for optimal activity. Increasing the size of the C-2 substituent of the aniline at C-4 of 2a from chloro to bromo to iodo resulted in a corresponding increase in Src inhibition. Furthermore, replacement of the 7-methoxy group of 2a with various 3-heteroalkylaminopropoxy groups provided increased inhibition of both Src enzymatic and cellular activity. Compound 25, which contains a 3-morpholinopropoxy group, had an IC(50) of 3.8 nM in the Src enzymatic assay and an IC(50) of 940 nM for the inhibition of Src-dependent cell proliferation.


Subject(s)
Aniline Compounds/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Morpholines/chemical synthesis , Nitriles/chemical synthesis , Quinolines/chemical synthesis , src-Family Kinases/antagonists & inhibitors , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Animals , Cell Division/drug effects , Cell Line , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Fibroblasts/cytology , Morpholines/chemistry , Morpholines/pharmacology , Nitriles/chemistry , Nitriles/pharmacology , Phosphorylation , Quinolines/chemistry , Quinolines/pharmacology , Rats
4.
Pflugers Arch ; 443 Suppl 1: S3-7, 2001.
Article in English | MEDLINE | ID: mdl-11845294

ABSTRACT

Cystic fibrosis (CF) is a complex disease affecting epithelial ion transport. There are not many diseases like CF that have triggered such intense research activities. The complexity of the disease is due to mutations in the CFTR protein, now known to be a Cl(-) channel and a regulator of other transport proteins. The various interactions and the large number of disease-causing CFTR mutations is the reason for a variable genotype-phenotype correlation and sometimes unpredictable clinical manifestation. Nevertheless, the research of the past 10 years has resulted in a tremendous increase in knowledge, not only in regard to CFTR but also in regard to molecular interactions and completely new means of ion channel and gene therapy.


Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/physiology , Cystic Fibrosis/metabolism , Cystic Fibrosis/physiopathology , Epithelial Sodium Channels , Humans , Sodium Channels/metabolism
5.
Am J Respir Cell Mol Biol ; 23(6): 755-61, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11104728

ABSTRACT

Cystic fibrosis (CF) airway epithelia are characterized by enhanced Na(+) absorption probably due to a lack of downregulation of epithelial Na(+) channels by mutant CF transmembrane conductance regulator. Extracellular nucleotides adenosine 5'-triphosphate (ATP) and uridine 5'-triphosphate (UTP) have been shown to activate alternative Ca(2+)-dependent Cl(-) channels in normal and CF respiratory epithelia. Recent studies suggest additional modulation of Na(+) absorption by extracellular nucleotides. In this study we examined the role of mucosal ATP and UTP in regulating Na(+) transport in native human upper airway tissues from patients with 16 patients with CF and 32 non-CF control subjects. To that end, transepithelial voltage and equivalent short-circuit current (I(SC)) were assessed by means of a perfused micro-Ussing chamber. Mucosal ATP and UTP caused an initial increase in lumen-negative I(SC) that was followed by a sustained decrease of I(sc) in both non-CF and CF tissues. The amiloride-sensitive portion of I(SC) was inhibited significantly in normal and CF tissues in the presence of either ATP or UTP. Both basal Na(+) transport and nucleotide-dependent inhibition of amiloride-sensitive I(SC) were significantly enhanced in CF airways compared with non-CF. Nucleotide-mediated inhibition of Na(+) absorption was attenuated by pretreatment with the Ca(2+)-adenosine triphosphatase inhibitor cyclopiazonic acid but not by inhibition of protein kinase C with bisindolylmaleimide. These data demonstrate sustained inhibition of Na(+) transport in non-CF and CF airways by mucosal ATP and UTP and suggest that this effect is mediated by an increase of intracellular Ca(2+). Because ATP and UTP inhibit Na(+) absorption and stimulate Cl(-) secretion simultaneously, extracellular nucleotides could have a dual therapeutic effect, counteracting the ion transport defect in CF lung disease.


Subject(s)
Amiloride/pharmacology , Cystic Fibrosis/metabolism , Epithelium/drug effects , Nasal Cavity/drug effects , Nucleotides/pharmacology , Sodium/pharmacokinetics , Absorption/drug effects , Adenosine Triphosphate/pharmacology , Adolescent , Adult , Aged , Calcium/metabolism , Child , Child, Preschool , Enzyme Inhibitors/pharmacology , Epithelium/metabolism , Female , Humans , Indoles/pharmacology , Male , Maleimides/pharmacology , Middle Aged , Nasal Cavity/metabolism , Protein Kinase C/antagonists & inhibitors , Signal Transduction , Uridine Triphosphate/pharmacology
6.
Bioorg Med Chem Lett ; 10(21): 2477-80, 2000 Nov 06.
Article in English | MEDLINE | ID: mdl-11078204

ABSTRACT

Src is a nonreceptor tyrosine kinase involved in signaling pathways that control proliferation, migration, and angiogenesis. Increased Src expression and activity are associated with an increase in tumor malignancy and poor prognosis. Several quinolines and quinazolines were identified as potent and selective inhibitors of Src kinase activity.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Quinazolines/chemical synthesis , Quinolines/chemical synthesis , src-Family Kinases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme-Linked Immunosorbent Assay , Humans , Molecular Structure , Quinazolines/chemistry , Quinazolines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Structure-Activity Relationship
7.
Nat Med ; 6(9): 1024-8, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10973323

ABSTRACT

A combination of two drugs afforded remarkable protection from intestinal neoplasia in APC(Min/+) mice, a murine model of human familial adenomatous polyposis (FAP). One of the drugs was sulindac, a prototypical non-steroidal anti-inflammatory drug with established chemopreventative activity. The second drug was EKI-569, a newly developed, irreversible inhibitor of the epidermal growth factor receptor kinase. Although 100% of the untreated APC(Min/+) mice developed approximately 20 polyps, nearly half the mice treated with these two agents developed no polyps at all. These results suggest a powerful strategy for the chemoprevention of human colonic neoplasia.


Subject(s)
Adenomatous Polyposis Coli/prevention & control , Antineoplastic Agents/therapeutic use , Organic Chemicals , Sulindac/therapeutic use , Aminoquinolines , Aniline Compounds , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Drug Therapy, Combination , Enzyme Inhibitors/therapeutic use , ErbB Receptors/antagonists & inhibitors , Mice , Mice, Mutant Strains , Quinazolines/therapeutic use
8.
J Med Chem ; 43(17): 3244-56, 2000 Aug 24.
Article in English | MEDLINE | ID: mdl-10966743

ABSTRACT

The synthesis and SAR of a series of 4-anilino-6, 7-dialkoxyquinoline-3-carbonitrile inhibitors of epidermal growth factor receptor (EGF-R) kinase are described. Condensation of 3, 4-dialkoxyanilines with ethyl (ethoxymethylene)cyanoacetate followed by thermal cyclization gave, regiospecifically, 6,7-dialkoxy-4-oxo-1, 4-dihydroquinoline-3-carbonitriles. Chlorination (POCl(3)) followed by the reaction with substituted anilines furnished the 4-anilino-6, 7-dialkoxyquinoline-3-carbonitrile inhibitors of EGF-R kinase. An alternate synthesis of these compounds starts with a methyl 3, 4-dialkoxybenzoate. Nitration followed by reduction (Fe, NH(4)Cl, MeOH-H(2)O) gave a methyl 2-amino-4,5-dialkoxybenzoate. Amidine formation using DMF-acetal followed by cyclization using LiCH(2)CN furnished a 6,7-dialkoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile, which was transformed as before. Compounds containing acid, ester, amide, carbinol, and aldehyde groups at the 3-position of the quinoline ring were also prepared for comparison, as were several 1-anilino-6,7-dimethoxyisoquinoline-4-carbonitriles. The compounds were evaluated for their ability to inhibit the autophosphorylation of the catalytic domain of EGF-R. The SAR of these inhibitors with respect to the nature of the 6,7-alkoxy groups, the aniline substituents, and the substituent at the 3-position was studied. The compounds were further evaluated for their ability to inhibit the growth of cell lines that overexpress EGF-R or HER-2. It was found that 4-anilinoquinoline-3-carbonitriles are effective inhibitors of EGF-R kinase with activity comparable to the 4-anilinoquinazoline-based inhibitors. A new homology model of EGF-R kinase was constructed based on the X-ray structures of Hck and FGF receptor-1 kinase. The model suggests that with the quinazoline-based inhibitors, the N3 atom is hydrogen-bonded to a water molecule which, in turn, interacts with Thr 830. It is proposed that the quinoline-3-carbonitriles bind in a similar manner where the water molecule is displaced by the cyano group which interacts with the same Thr residue.


Subject(s)
Aniline Compounds/chemical synthesis , Antineoplastic Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , ErbB Receptors/antagonists & inhibitors , Nitriles/chemical synthesis , Quinazolines/chemical synthesis , Quinolines/chemical synthesis , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Fluorometry , Humans , Inhibitory Concentration 50 , Models, Molecular , Nitriles/chemistry , Nitriles/pharmacology , Phosphorylation , Quinazolines/chemistry , Quinazolines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Structure-Activity Relationship , Tumor Cells, Cultured
9.
Am J Respir Cell Mol Biol ; 23(3): 283-9, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10970817

ABSTRACT

Ion transport defects underlying cystic fibrosis (CF) lung disease are characterized by impaired cyclic adenosine monophosphate (cAMP)-dependent Cl(-) conductance. Activation of Cl(-) secretion in airways depends on simultaneous activation of luminal Cl(-) channels and basolateral K(+) channels. We determined the role of basolateral K(+) conductance in cAMP- dependent Cl(-) secretion in native human airway epithelium obtained from non-CF and CF patients. CF tissues showed typical alterations of short-circuit currents with enhanced amiloride-sensitive Na(+) conductance and defective cAMP-mediated Cl(-) conductance. In non-CF tissues, Cl(-) secretion was significantly inhibited by the chromanol 293B (10 micromol/liter), a specific inhibitor of K(V)LQT1 K(+) channels. Inhibition was increased after cAMP-dependent stimulation. Similar effects were obtained with Ba(2+) (5 mmol/liter). In patch-clamp experiments with a human bronchial epithelial cell line, stimulation with forskolin (10 micromol/liter) simultaneously activated Cl(-) and K(+) conductance. The K(+) conductance was reversibly inhibited by Ba(2+) and 293B. Analysis of reverse-transcribed messenger RNA from non-CF and CF airways showed expression of human K(V)LQT1. We conclude that the K(+) channel K(V)LQT1 is important in maintaining cAMP-dependent Cl(-) secretion in human airways. Activation of K(V)LQT1 in CF airways in parallel with stimulation of residual CF transmembrane conductance regulator Cl(-) channel activity or alternative Cl(-) channels could help to circumvent the secretory defect.


Subject(s)
Bronchi/metabolism , Chlorides/metabolism , Cyclic AMP/metabolism , Potassium Channels, Voltage-Gated , Potassium Channels/metabolism , Respiratory Mucosa/metabolism , 1-Methyl-3-isobutylxanthine/pharmacology , Amiloride/pharmacology , Biological Transport/drug effects , Biological Transport/physiology , Bronchi/cytology , Cell Line, Transformed , Chromans/pharmacology , Colforsin/pharmacology , Cystic Fibrosis/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Diuretics/pharmacology , Gene Expression/physiology , Humans , KCNQ Potassium Channels , KCNQ1 Potassium Channel , Membrane Potentials/drug effects , Membrane Potentials/physiology , Patch-Clamp Techniques , Phosphodiesterase Inhibitors/pharmacology , Potassium/metabolism , Potassium Channel Blockers , Potassium Channels/genetics , Respiratory Mucosa/cytology , Sulfonamides/pharmacology
10.
Br J Pharmacol ; 130(8): 1884-92, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10952679

ABSTRACT

The flavonoid genistein has been shown to activate a Cl(-) conductance in various cell types expressing CFTR. We examined if similar effects can be observed when genistein is applied to native ex vivo tissues from human respiratory tract and rectum. We further compared the effects when genistein was applied to oocytes of Xenopus laevis expressing CFTR. In oocytes, both wtCFTR and DeltaF508-CFTR were activated by genistein while both cyclic AMP (K(v)LQT1) and Ca(2+) (SK4) activated K(+) channels were inhibited at high concentrations of genistein. Biopsies from nasal polyps and rectal mucosa were obtained from normal individuals (non-CF) and CF patients and in the presence of amiloride (10 micromol l(-1); mucosal side) the effects of genistein were assessed using a perfused Ussing chamber. In non-CF airway epithelia, genistein (50 micromol l(-1); mucosal side) increased lumen negative I(sc) but had no additional effects on tissues pre-stimulated with IBMX and forskolin (100 micromol l(-1) and 1 micromol l(-1); both sides). In non-CF rectal biopsies, in the presence of amiloride (10 micromol l(-1); mucosal side) and indomethacin (10 micromol l(-1); basolateral side), genistein increased lumen negative I(sc) and enabled cholinergic (carbachol; CCH, 100 micromol l(-1); basolateral side) stimulation of Cl(-) secretion indicating activation of luminal CFTR Cl(-) channels. However, after stimulation with IBMX/forskolin, genistein induced opposite effects and significantly inhibited CCH activated I(sc). In CF airway and intestinal tissues genistein failed to induce Cl(-) secretion. Thus, genistein is able to activate luminal CFTR Cl(-) conductance in non-CF tissues and mutant CFTR in oocytes. However, additional inhibitory effects on basolateral K(+) conductance and missing effects in native CF tissues do not support the use for pharmacological intervention in CF.


Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/drug effects , Cystic Fibrosis/physiopathology , Epithelium/drug effects , Genistein/pharmacology , Ion Channels/drug effects , 1-Methyl-3-isobutylxanthine/pharmacology , Adolescent , Adult , Aged , Amiloride/pharmacology , Animals , Child , Child, Preschool , Colforsin/pharmacology , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Dose-Response Relationship, Drug , Epithelium/physiopathology , Female , Gene Expression , Humans , Ion Channels/genetics , Ion Transport/drug effects , Membrane Potentials/drug effects , Middle Aged , Mutation , Nasal Cavity/drug effects , Nasal Cavity/physiopathology , Oocytes , Rectum/drug effects , Rectum/physiopathology , Sodium Channels/drug effects , Xenopus
11.
Am J Physiol Gastrointest Liver Physiol ; 278(4): G617-24, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10762616

ABSTRACT

Rectal biopsies from cystic fibrosis (CF) patients show defective cAMP-activated Cl(-) secretion and an inverse response of the short-circuit current (I(sc)) toward stimulation with carbachol (CCh). Alternative Cl(-) channels are found in airway epithelia and have been attributed to residual Cl(-) secretion in CF colon. The aim of the present study was to investigate ion conductances causing reversed I(sc) upon cholinergic stimulation. Furthermore, the putative role of an alternative Ca(2+)-dependent Cl(-) conductance in human distal colon was examined. Cholinergic ion secretion was assessed in the absence and presence of cAMP-dependent stimulation. Transepithelial voltage and I(sc) were measured in rectal biopsies from non-CF and CF individuals by means of a perfused micro-Ussing chamber. Under baseline conditions, CCh induced a positive I(sc) in CF rectal biopsies but caused a negative I(sc) in non-CF subjects. The CCh-induced negative I(sc) in non-CF biopsies was gradually reversed to a positive response by incubating the biopsies in indomethacin. The positive I(sc) was significantly enhanced in CF and was caused by activation of a luminal K(+) conductance, as shown by the use of the K(+) channel blockers Ba(2+) and tetraethylammonium. Moreover, a cAMP-dependent luminal K(+) conductance was detected in CF individuals. We conclude that the cystic fibrosis transmembrane conductance regulator is the predominant Cl(-) channel in human distal colon. Unlike human airways, no evidence was found for an alternative Cl(-) conductance in native tissues from CF patients. Furthermore, we demonstrated that both Ca(2+)- and cAMP-dependent K(+) secretion are present in human distal colon, which are unmasked in rectal biopsies from CF patients.


Subject(s)
Chlorides/metabolism , Cholinergic Fibers/metabolism , Cystic Fibrosis/metabolism , Potassium/metabolism , Rectum/metabolism , Adolescent , Adult , Biopsy , Carbachol/pharmacology , Child , Child, Preschool , Cholinergic Agonists/pharmacology , Cyclic AMP/antagonists & inhibitors , Cyclic AMP/biosynthesis , Cyclic AMP/physiology , Cyclooxygenase Inhibitors/pharmacology , Cystic Fibrosis/genetics , Cystic Fibrosis/pathology , Humans , Indomethacin/pharmacology , Infant , Middle Aged , Phenotype , Rectum/pathology , Reference Values
12.
Bioorg Med Chem Lett ; 10(24): 2825-8, 2000 Dec 18.
Article in English | MEDLINE | ID: mdl-11133101

ABSTRACT

A series of 3-cyano-4-(phenoxyanilino)cyanoquinolines has been prepared as MEK (MAP kinase kinase) inhibitors. The best activity is seen with alkoxy groups at both the 6- and 7-positions. The lead compounds show low nanomolar IC50's against MAP kinase kinase, and have potent inhibitory activity in tumor cells.


Subject(s)
Antineoplastic Agents/chemical synthesis , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Nitriles/pharmacology , Quinolines/pharmacology , Aniline Compounds/chemical synthesis , Aniline Compounds/pharmacology , Antineoplastic Agents/pharmacology , Cell Division/drug effects , Colonic Neoplasms/pathology , Enzyme-Linked Immunosorbent Assay , Humans , Inhibitory Concentration 50 , Nitriles/chemical synthesis , Quinolines/chemical synthesis , Structure-Activity Relationship , Tumor Cells, Cultured
13.
Biochem Pharmacol ; 57(8): 917-25, 1999 Apr 15.
Article in English | MEDLINE | ID: mdl-10086326

ABSTRACT

It has been shown previously that 4-anilino quinazolines compete with the ability of ATP to bind the epidermal growth factor receptor (EGF-R), inhibit EGF-stimulated autophosphorylation of tyrosine residues in EGF-R, and block EGF-mediated growth. Since millimolar concentrations of ATP in cells could reduce the efficacy of 4-anilino quinazolines in cells and the activity of these compounds would not be sustained once they were removed from the body, we reasoned that irreversible inhibitors of EGF-R might improve the activity of this series of compounds in animals. Molecular modeling of the EGF-R kinase domain was used to design irreversible inhibitors. We herein describe one such inhibitor: N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]2-butynamide, known as CL-387,785. This compound covalently bound to EGF-R. It also specifically inhibited kinase activity of the protein (IC50 = 370+/-120 pM), blocked EGF-stimulated autophosphorylation of the receptor in cells (ic50 approximately 5 nM), inhibited cell proliferation (IC50 = 31-125 nM) primarily in a cytostatic manner in cell lines that overexpress EGF-R or c-erbB-2, and profoundly blocked the growth of a tumor that overexpresses EGF-R in nude mice (when given orally at 80 mg/kg/day for 10 days, daily). We conclude that CL-387,785 is useful for studying the interaction of small molecules with EGF-R and may have clinical utility.


Subject(s)
Enzyme Inhibitors/pharmacology , ErbB Receptors/antagonists & inhibitors , Quinazolines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Cycle/drug effects , Cell Division/drug effects , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , ErbB Receptors/metabolism , Female , Mice , Mice, Nude , Models, Molecular , Neoplasm Transplantation , Neoplasms, Experimental/drug therapy , Phosphorylation/drug effects , Quinazolines/chemical synthesis , Tumor Cells, Cultured
14.
J Infect Dis ; 169(1): 150-6, 1994 Jan.
Article in English | MEDLINE | ID: mdl-8277176

ABSTRACT

Experiments using a murine model of heat-killed Staphylococcus aureus-induced gram-positive bacterial sepsis indicate that the lethal bacterial effects can be prevented if mice are pretreated with CL 184,005, a platelet-activating factor (PAF) antagonist. CL 184,005 was ineffective when administered after bacterial challenge. Plasma of mice pretreated with CL 184,005 contained significantly less tumor necrosis factor (TNF), suggesting that CL 184,005 interferes with TNF synthesis induced by S. aureus. Spleen-associated TNF protein was also decreased by pretreatment with CL 184,005. Although TNF levels were significantly decreased in mice treated with CL 184,005, interleukin-6 levels in serum were significantly increased. Athymic mice were also susceptible to the lethal effects of S. aureus, suggesting that T cells were not involved. When rats rendered hypotensive with S. aureus were treated with CL 184,005, their blood pressure was normalized. Mice treated with enterotoxin B were not protected if they were pretreated with CL 184,005; however, TNF levels in these mice were significantly lower, suggesting that mediators other than PAF and TNF may contribute to the lethal effects of enterotoxin.


Subject(s)
Organophosphorus Compounds/therapeutic use , Platelet Activating Factor/antagonists & inhibitors , Staphylococcal Infections/drug therapy , Thiazoles/therapeutic use , Animals , Blood Pressure/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Enterotoxins/pharmacology , Interleukin-6/biosynthesis , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Organophosphorus Compounds/pharmacology , Platelet Activating Factor/physiology , Staphylococcal Infections/etiology , Thiazoles/pharmacology , Time Factors , Tumor Necrosis Factor-alpha/biosynthesis
15.
Inflammation ; 17(3): 245-61, 1993 Jun.
Article in English | MEDLINE | ID: mdl-8330926

ABSTRACT

Several 1-alkyl ether lipids were studied for their ability to inhibit PLA2 and antagonize PAF responses. Studies with synthetic micellar substrate (1-stearyl-2-arachidonyl phosphocholine), at concentrations ranging from 0.02 to 1000 microM, demonstrate that CL 118326 inhibits porcine pancreatic PLA2 in vitro. As the substrate concentration increases, there is a dose-dependent increase in the IC50 value (IC50 ranges: 1.6-84.6 micrograms/ml or 2.6-137 microM). CL 118326 inhibits mammalian pancreatic PLA2, but not snake or bee venom PLA2. CL 118326 inhibits thrombin (IC50 = 7.9 microM), but not Na arachidonate- (IC50 > 100 microM) induced platelet aggregation, indicative of inhibition of cellular PLA2. CL 118326 inhibits other PLA2-dependent processes such as antigen-induced leukotriene (LTC4) release (IC50 = 2.3 micrograms/ml or 3.8 microM) and histamine release (IC50 = 1.4 micrograms/ml or 2.2 microM) in basophil-enriched WBCs. Intradermal coinjection of CL 118326 (10 micrograms) with PLA2 into guinea pig skin inhibits pancreatic PLA2-induced increase in vascular permeability and leakage, but not snake or bee venom PLA2-induced leakage. CL 118326 shows no PAF-like agonist activity in stimulating rabbit platelet-rich plasma. It inhibits PAF-induced aggregation (IC50 = 5.8 microM), but not ADP-induced aggregation. CL 118326 has greater efficacy as a PLA2 inhibitor than as a PAF antagonist since the IC50-substrate concentration ratio for PLA2 inhibition is < or = 1.0 at substrate concentrations of 10-1000 microM while the IC50-agonist ratio for PAF antagonism is > 100. Results for four other compounds related to CL 118326 are also presented.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Ethylene Glycols/pharmacology , Phospholipases A/antagonists & inhibitors , Platelet Activating Factor/metabolism , Quaternary Ammonium Compounds/pharmacology , Animals , Bee Venoms/enzymology , Capillary Permeability/drug effects , Dose-Response Relationship, Drug , Elapid Venoms/enzymology , Guinea Pigs , Humans , Pancreas/enzymology , Phospholipases A2 , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/pharmacology , Rats , Species Specificity , Structure-Activity Relationship , Swine/metabolism
16.
J Med Chem ; 36(5): 580-90, 1993 Mar 05.
Article in English | MEDLINE | ID: mdl-8496938

ABSTRACT

A series of platelet activating factor (PAF) antagonists containing a quaternary pyridinium ring connected through an amide, imide, or carbamate linkage to a substituted aromatic ring was prepared. Of these compounds, those containing a branched imide linkage of the form (CON-(COCH3)CH2, 37-51, and 59) generally showed excellent PAF antagonist properties in vitro. Structure-activity relationships within this series of compounds were studied extensively with respect to substituents and the position of substitution in both the aromatic and pyridinium rings. Several of these compounds (40 and 44) showed in vitro PAF antagonism at less than 0.1 microM and are as potent as CV-6209, the most potent PAF antagonist reported in the literature. Less active PAF antagonists were those bearing simple amide linkages (20-23, 27-29, and 31-35), linear imide linkages (62-63), or carbamate linkages (66 and 68), between the two aromatic rings. A number of our PAF antagonists were tested in vivo in mice and rabbits for their ability to protect these animals against a lethal injection of PAF. Those antagonists that are particularly potent (IC50 < 0.1 microM) provide excellent protection against an LD97 dose of PAF in rabbits. The relationships between structure and activity in vitro and in vivo are presented and compared to literature standards.


Subject(s)
Platelet Activating Factor/antagonists & inhibitors , Pyridinium Compounds/chemical synthesis , Amides/chemistry , Amides/pharmacology , Animals , Carbamates/chemistry , Carbamates/pharmacology , Imides/chemistry , Imides/pharmacology , Mice , Molecular Structure , Platelet Aggregation/drug effects , Pyridinium Compounds/chemistry , Pyridinium Compounds/pharmacology , Rabbits , Structure-Activity Relationship
17.
J Med Chem ; 35(26): 4779-89, 1992 Dec 25.
Article in English | MEDLINE | ID: mdl-1336052

ABSTRACT

A series of bis-aryl amide (13-57 and 66-81) and bis-aryl urea (58 and 85) antagonists of platelet-activating factor (PAF) was prepared that contain, separating the two aromatic rings, linear amide linkages of the form -(CH2)nCONH- (n = 0-2), -OCH2CONH-, and -(CH2)nNHCO- (n = 0-1), branched amide linkages of the form -(CH2)nN(COR)- (n = 1-3, R = CH3 or n-C3H7), and -N(COCH3)CH2-, and urea linkages of the form -NHCONH- and -CH2N(CONHCH3)-. These compounds were examined for their ability to inhibit PAF-induced platelet aggregation of rabbit platelets. These in vitro data were compared to similar data obtained for a number of known PAF antagonists. The compounds were evaluated in vivo, in the mouse, for their ability to prevent death induced by a lethal challenge of PAF. The relationships between the biological activity and the nature, lipophilicity, and position of substituents of the aromatic rings were studied. Best activity was observed for compounds having linkages of the type -CH2CONH-, -CH2N(COR)-, and -CH2NHCO-. Many of these compounds inhibit PAF-induced platelet aggregation with IC50's under 1 microM.


Subject(s)
Amides/chemical synthesis , Platelet Activating Factor/analogs & derivatives , Platelet Membrane Glycoproteins , Receptors, Cell Surface/drug effects , Receptors, G-Protein-Coupled , Urea/analogs & derivatives , Amides/chemistry , Amides/pharmacology , Animals , Female , Mice , Platelet Activating Factor/antagonists & inhibitors , Platelet Aggregation/drug effects , Rabbits , Structure-Activity Relationship
18.
Antimicrob Agents Chemother ; 36(9): 1971-7, 1992 Sep.
Article in English | MEDLINE | ID: mdl-1416889

ABSTRACT

The effect of CL 184,005, a potent and specific platelet-activating factor antagonist, has been examined in a variety of animal models relevant to gram-negative bacterial sepsis. Pretreatment of mice with CL 184,005 protected them from the lethal effects of platelet-activating factor. When rats or primates rendered hypotensive with endotoxin were treated with CL 184,005, blood pressure was normalized. Pretreatment of rats with CL 184,005 protected them from the gastrointestinal lesions induced by endotoxin. Pretreatment of rats and mice with CL 184,005 protected them from the lethal effects of endotoxin. Plasma tumor necrosis factor levels in endotoxin-treated mice were lower when the mice were pretreated with CL 184,005. These observations suggest that CL 184,005 may be potentially useful in the treatment of gram-negative bacterial sepsis, and the agent is undergoing clinical evaluation.


Subject(s)
Gram-Negative Bacterial Infections/drug therapy , Organophosphorus Compounds/therapeutic use , Platelet Activating Factor/antagonists & inhibitors , Thiazoles/therapeutic use , Animals , Blood Pressure/drug effects , Female , Gram-Negative Bacterial Infections/microbiology , Humans , Hypotension/physiopathology , Interleukin-6/biosynthesis , Macaca fascicularis , Male , Mice , Mice, Inbred BALB C , Mice, Inbred ICR , Permeability , Platelet Activating Factor/toxicity , Rabbits , Rats , Rats, Wistar , Tumor Necrosis Factor-alpha/biosynthesis
20.
J Med Chem ; 35(9): 1650-62, 1992 May 01.
Article in English | MEDLINE | ID: mdl-1578493

ABSTRACT

A series of aryl phosphoglyceride (3, 19-61) and bis-aryl phosphate (67-135) antagonists of platelet activating factor (PAF) were prepared. A group of four bifunctional phosphorus reagents (5a-c and 7) were developed that allowed the preparation of these aryl phosphates in which the position of aromatic substitution can be varied. These compounds were examined for their ability to inhibit PAF-induced platelet aggregation of rabbit platelets. Selected compounds were also evaluated for their ability to displace [3H]PAF from its receptor on rabbit platelets. These in vitro data were compared to similar data obtained for a number of known PAF antagonists. The compounds were evaluated in vivo, in both the mouse and rabbit, for their ability to prevent death induced by a lethal challenge of PAF. The relationships between the biological activity and the nature, lipophilicity, and position of substituents of the aromatic rings were studied. Compound 105 (CL 184005) has been selected to undergo further development as a potential therapeutic agent for the treatment of septic shock in man.


Subject(s)
Platelet Activating Factor/analogs & derivatives , Animals , Female , Male , Mice , Platelet Activating Factor/antagonists & inhibitors , Platelet Activating Factor/pharmacology , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/pharmacology , Rabbits , Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL
...