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, CulturedABSTRACT
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, CulturedSubject(s)
Arginine Vasopressin/antagonists & inhibitors , Receptors, Vasopressin/metabolism , Administration, Oral , Animals , Arginine Vasopressin/deficiency , Azepines/administration & dosage , Azepines/chemical synthesis , Azepines/metabolism , Azepines/pharmacology , Benzamides/administration & dosage , Benzamides/chemical synthesis , Benzamides/metabolism , Benzamides/pharmacology , Blood Platelets/metabolism , Body Water/metabolism , Cell Line , Cell Membrane/metabolism , Dogs , Fibroblasts/drug effects , Fibroblasts/metabolism , Humans , Kidney/metabolism , Liver/metabolism , Osmolar Concentration , Pyrroles , Rats , Sodium/blood , Structure-Activity Relationship , Urine/chemistryABSTRACT
The role of immunologically released mediators, such as histamine, leukotrienes, and platelet-activating factor, is well-established for asthma and other allergic disorders. Developing therapeutic agents which would block mediator release from mast cells and other relevant cell types would provide a rational approach to asthma therapy. Using human basophil as a screen, a series of 4-aryl-2-(phenylamino)pyrimidines was found which inhibited mediator release. These compounds were prepared by condensing acetyl heterocycles with dimethylformamide dimethyl acetal to form enaminones which are cyclized with aryl guanidines to give pyrimidines. After examining a large number of analogs, N-[3-(1H-imidazol-1-yl)phenyl]-4-(2-pyridinyl)-2- pyrimidinamine (1-27) was chosen for toxicological evaluation.
Subject(s)
Histamine Antagonists/chemical synthesis , Imidazoles/chemical synthesis , Pyrimidines/chemical synthesis , Animals , Basophils/drug effects , Basophils/metabolism , Female , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Lethal Dose 50 , Macaca mulatta , Male , Mice , Passive Cutaneous Anaphylaxis/drug effects , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The preparation and biological activities of a series of pyrido[3,4-e]-1,2,4-triazines, 1,2,4-triazino[5,6-c]quinolines, and related fused triazines are described. Methyl, amino, and acylamino substituents were placed in the pyridyl ring of the former system. Other structural modifications included various alkyl, cycloalkyl, substituted phenyl, and heterocyclic groups in the 3-position of these ring systems. In agar dilution assays, actives in this series inhibited strains of Candida, Aspergillus, Mucor, and Trychophyton species at MIC's of less than or equal to 16 micrograms/mL.
Subject(s)
Antifungal Agents/pharmacology , Heterocyclic Compounds/pharmacology , Pyridines/pharmacology , Quinolines/pharmacology , Triazines/pharmacology , Antifungal Agents/chemical synthesis , Candida/drug effects , Chemical Phenomena , Chemistry , Heterocyclic Compounds/chemical synthesis , Pyridines/chemical synthesis , Quinolines/chemical synthesis , Triazines/chemical synthesisABSTRACT
The synthesis of a series of analogues in which the carboxylic acid group of cetaben is replaced by carboxylate ester, carboxamide, or a variety of other substituent groups is described. Also reported are the syntheses of analogues in which the phenyl ring of cetaben is either modified by the presence of additional substituents or replaced entirely by another moiety. Structure-activity relationships of these compounds both as hypolipidemic agents and as inhibitors of the enzyme fatty acyl-CoA:cholesterol acyltransferase (ACAT) are discussed. Analogue syntheses designed to produce compounds that would be better absorbed orally than cetaben failed to yield any congeners of enhanced biological activity. In contrast, analogue syntheses directed toward non carboxylic acids of similar acidity to cetaben produced a very active class of sulfonamides.
Subject(s)
4-Aminobenzoic Acid/chemical synthesis , Aminobenzoates/chemical synthesis , Arteriosclerosis/drug therapy , 4-Aminobenzoic Acid/pharmacology , 4-Aminobenzoic Acid/therapeutic use , Animals , Benzoates/therapeutic use , Drug Evaluation, Preclinical , Hyperlipidemias/drug therapy , Male , Methods , Rats , Rats, Inbred Strains , Sterol O-Acyltransferase/antagonists & inhibitors , Sterols/blood , Structure-Activity Relationship , Triglycerides/blood , para-AminobenzoatesABSTRACT
The syntheses of a series of (aralkylamino)- and (alkylamino)benzoic acids, as well as the corresponding esters and sodium salts, are described. The compounds were evaluated in vivo in rats for serum sterol and triglyceride lowering activity and in vitro for activity in inhibiting the principle cholesterol-esterifying enzyme of the arterial wall, fatty acyl-CoA:cholesterol acyltransferase (ACAT). Based on a combination of these two activities, cataben sodium (150) was selected for development as a hypolipidemic and potential antiatherosclerotic agent.
Subject(s)
4-Aminobenzoic Acid/chemical synthesis , Acyltransferases/antagonists & inhibitors , Aminobenzoates/chemical synthesis , Arteriosclerosis/drug therapy , Sterol O-Acyltransferase/antagonists & inhibitors , 4-Aminobenzoic Acid/pharmacology , 4-Aminobenzoic Acid/therapeutic use , Animals , Drug Evaluation, Preclinical , Hyperlipidemias/drug therapy , Indicators and Reagents , Male , Methods , Rats , Rats, Inbred Strains , Sterols/blood , Structure-Activity Relationship , Triglycerides/blood , para-AminobenzoatesABSTRACT
Several 3-deoxy opioids and 3,6-dideoxydihydromorphine was synthesized to ascertain the effect of the phenolic hydroxyl group on antinociceptive potency and receptor binding affinity. Catalytic reduction of the 3-tetrazolyl ether derivatives of dihydromorphine provided the entry into the 3-deoxydihydro series. The prototype, 3-deoxymorphine, was prepared by lithium aluminum hydride reduction of 3-deoxy-N-carbethoxymorphinone, obtained via its 7-(phenylseleno) derivative. 3-Deoxydihydromorphinone and 3,6-dideoxydihydromorphine were found to be about as potent as, or more potent than, morphine in standard antiociceptive assays. Each of them, however, was less potent than the comparable 3-hydroxy analogue, and their binding affinity to the opiate receptor was substantially decreased. The epoxy ring in 3.6-dideoxydihydromorphine was found to increase the antinociceptive potency of the compound.
Subject(s)
Analgesics , Morphine Derivatives/pharmacology , Receptors, Opioid/drug effects , Animals , Chemical Phenomena , Chemistry , Mice , Morphine Derivatives/chemical synthesis , Structure-Activity RelationshipABSTRACT
A series of analogues of insect juvenile hormone (four geometric isomers of methyl epoxyfarnesenate, several para-substituted epoxygeranyl phenyl ethers, and epoxyfarnesol and its acetate and haloacetate derivatives) was prepared to investigate the binding specificity of the hemolymph juvenile hormone binding protein from the tobacco hornworm Manduct sexta. The relative binding affinities were determined by a competition assay against radiolabeled methyl (E,E)-3,11-dimethyl-7-ethyl-cis-10,11-epoxytrideca-2,6-dienoate (JH I). The ratio of dissociation constants was estimated by plotting competitor data according to a linear transformation of the dissociation equations describing competition of two ligands for a binding protein. The importance of the geometry of the sesquiterpene hydrocarbon chain is indicated by the fact that the binding affinity is decreased as Z (cis) double bonds are substituted for E (trans) double bonds in the methyl epoxyfarnesenate series; the unepoxidized analogues do not bind. A carboxylic ester function is important although its orientation can be reversed, as indicated by the good binding of epoxyfarnesyl acetate. In the monoterpene series, methyl epoxygeranoate shows no affinity for the binding protein, but substitution of a phenyl or p-carbomethoxyphenyl ether for the ester function imparts a low, but significant affinity. These data taken together with earlier results indicate that the binding site for juvenile hormone in the hemolymph binding protein is characterized by a sterically defined hydrophobic region with polar sites that recognize the epoxide and the ester functions.