- PEPTIDE AND SMALL MOLECULE AGONISTS OF EPHA AND THEIR USES
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A method of treating cancer in a subject includes administering to the subject a therapeutically effective amount of a compound, the small molecule having a general formula: A-L-X-Z (I).
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Paragraph 00226; 00240; 00259
(2019/01/21)
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- Design and synthesis of small molecule agonists of EphA2 receptor
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Ligand-independent activation of EphA2 receptor kinase promotes cancer metastasis and invasion. Activating EphA2 receptor tyrosine kinase with small molecule agonist is a novel strategy to treat EphA2 overexpressing cancer. In this study, we performed a lead optimization of a small molecule Doxazosin that was identified as an EphA2 receptor agonist. 33 new analogs were developed and evaluated; a structure?activity relationship was summarized based on the EphA2 activation of these derivatives. Two new derivative compounds 24 and 27 showed much improved activity compared to Doxazosin. Compound 24 possesses a bulky amide moiety, and compound 27 has a dimeric structure that is very different to the parental compound. Compound 27 with a twelve-carbon linker of the dimer activated the kinase and induced receptor internalization and cell death with the best potency. Another dimer with a six-carbon linker has significantly reduced potency compared to the dimer with a longer linker, suggesting that the length of the linker is critical for the activity of the dimeric agonist. To explore the receptor binding characteristics of the new molecules, we applied a docking study to examine how the small molecule binds to the EphA2 receptor. The results reveal that compounds 24 and 27 form more hydrogen bonds to EphA2 than Doxazosin, suggesting that they may have higher binding affinity to the receptor.
- Petty, Aaron,Idippily, Nethrie,Bobba, Viharika,Geldenhuys, Werner J.,Zhong, Bo,Su, Bin,Wang, Bingcheng
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p. 1261 - 1276
(2017/11/27)
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- Targeting Influenza A Virus RNA Promoter
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The emergence of drug-resistant strains of influenza virus makes exploring new classes of inhibitors that target universally conserved viral targets a highly important goal. The influenza A viral genome is made up of eight single-stranded RNA-negative segments. The RNA promoter, consisting of the conserved sequences at the 3′ and 5′ end of each RNA genomic segment, is universally conserved among influenza A virus strains and in all segments. Previously, we reported on the identification and NMR structure of DPQ (6,7-dimethoxy-2-(1-piperazinyl)-4-quinazolinamine) (compound 1) in complex with the RNA promoter. Here, we report on additional screening and SAR studies with compound 1, including ex vivo anti-influenza activity assays, resulted in improved cellular activity against influenza A virus in the micromolar range.
- Bottini, Angel,De, Surya K.,Wu, Bainan,Tang, Changyan,Varani, Gabriele,Pellecchia, Maurizio
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p. 663 - 673
(2015/03/30)
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- THERAPY FOR COMPLICATIONS OF DIABETES
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A method for enhancing glycemic control and/or insulin sensitivity in a human subject having diabetic nephropathy and/or metabolic syndrome comprises administering to the subject a selective endothelin A (ETA) receptor antagonist in a glycemic control and/or insulin sensitivity enhancing effective amount. A method for treating a complex of comorbidities in an elderly diabetic human subject comprises administering to the subject a selective ETA receptor antagonist in combination or as adjunctive therapy with at least one additional agent that is (i) other than a selective ETA receptor antagonist and (ii) effective in treatment of diabetes and/or at least one of said comorbidities other than hypertension. A therapeutic combination useful in such a method comprises a selective ETA receptor antagonist and at least one antidiabetic, anti-obesity or antidyslipidemic agent other than a selective ETA receptor antagonist.
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- ANTIHYPERTENSIVE THERAPY
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A new use of darusentan is provided in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy with one or more drugs. The composition comprises darusentan in an amount providing a therapeutically effective daily dose; wherein (a) the composition is orally deliverable and/or (b) the daily dose of darusentan is effective to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures. Further provided is a new use of darusentan in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy, wherein the composition is administered adjunctively with at least one diuretic and at least one antihypertensive drug selected from ACE inhibitors, angiotensin II receptor blockers, beta-adrenergic receptor blockers and calcium channel blockers.
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- Method for treating resistant hypertension
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A method is provided for lowering blood pressure in a patient having clinically diagnosed resistant hypertension. The method comprises administering darusentan to the patient adjunctively with a baseline antihypertensive regimen that comprises administration of at least one diuretic and at least two antihypertensive drugs selected from at least two of (a) ACE inhibitors and angiotensin II receptor blockers, (b) beta-adrenergic receptor blockers and (c) calcium channel blockers. The darusentan is orally administered at a dose and frequency effective, in combination with the baseline regimen, to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures.
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- Parallel synthesis of N-arylpiperazines using polymer-assisted reactions
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A series of N-arylpiperazines were prepared in a parallel fashion using palladium-catalyzed cross-coupling, or nucleophilic aromatic displacement chemistries, and polymer-assisted sequestration and purification techniques as key steps.
- Duncton, Matthew A. J.,Roffey, Jonathan R. A.,Hamlyn, Richard J.,Adams, David R.
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p. 2549 - 2552
(2007/10/03)
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- Novel crystalline forms of prazosin hydrochloride
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The invention relates to novel and valuable crystalline forms of the hypotensive agent prazosin hydrochloride. The anhydrous α-form is preferred because it is relatively non-hygroscopic and hence possesses important advantages in handling and formulation. The polyhydrate form of prazosin hydrochloride is preferred because of its low, uniform rate of dissolution.
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- Process for preparing hypotensive 2-(4-aroylpiperazin-1-yl)-amino-6,7-dimethoxyquinazolines
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Certain 2-(4-aroylpiperazin-1-yl)-4-amino-6,7-dimethoxyquinazolines are prepared by a novel process wherein certain 2-(4-substituted-piperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline intermediates wherein said substituent is cyano, certain carbon-oxygen double bond containing groups or certain carbon-nitrogen double bond containing groups, are reacted with certain metalloaryl compounds followed by hydrolysis. The products are known hypotensive agents. Certain of the process intermediates are novel compounds.
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- Synthesis and identification of the major metabolites of prazosin formed in dog and rat
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The 6 O demethyl and 7 O demethyl analogues of the new antihypertensive drug prazosin [2 [4 (2 furoyl) piperazin 1 yl] 4 amino 6,7 dimethoxyquinazoline hydrochloride] have been unequivocally synthesized via separate ten step reaction sequences starting from isovanillin and vanillin, respectively. The 6 O demethyl derivative was found to be identical with the major prazosin metabolite formed in dog and rat, while the 7 O demethyl derivative was identical with another, less prevalent but significant metabolite. Two minor metabolites of prazosin, 2 (1 piperazinyl) 4 amino 6,7 dimethoxyquinazoline and 2,4 diamino 6,7 dimethoxyquinazoline, are also described. All four metabolites are less potent blood pressure lowering agents in dogs than prazosin but may contribute to its antihypertensive effect, since they account for a major portion of the administered dose.
- Althuis,Hess
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p. 146 - 149
(2007/10/05)
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- Process for hypotensive 4-amino-2-(piperazin-1-yl) quinazoline derivatives
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6,7-Dimethoxy-4-amino-2-(4-substituted piperazin-1-yl)-quinazolines and 6,7,8-trimethoxy-4-amino-2-(4-substituted piperazin-1-yl)quinazolines are produced by either: (1) reaction of the appropriate 4,5-dimethoxy substituted or 3,4,5-trimethoxy substituted 2-aminobenzonitrile with certain 1,4-disubstituted piperazines; or (2) reaction of the appropriate 4,5-dimethoxy substituted or 3,4,5-trimethoxy substituted 2-aminobenzamidine with the same 1,4-disubstituted piperazines. The products are known hypotensive agents.
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- 4-Amino-pyrimidine derivatives
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A process is described for the preparation of pyrimidine derivatives having therapeutic properties. They have the general formula: SPC1 Wherein A represents an alkylene or alkenylene grouping which together with the carbon atoms of the pyrimidine nucleus to which it is attached forms a homocyclic ring containing five to seven carbon atoms, which homocyclic ring may carry one or more halogen, lower alkyl and/or lower alkoxy substituents and R represents an amino, lower alkylamino or di(lower)alkylamino group, or a nitrogen-, oxygen- or sulphur-containing saturated or unsaturated mononuclear heterocyclic group linked to the pyrimidine ring either through a carbon atom or, when the group contains a nitrogen atom, either through the nitrogen atom or a carbon atom and are prepared by reacting a cycloaliphatic(A)oaminonitrile with a nitrile of the formula R-CN where A and R have the above meanings in the presence of a basic alkali metal-containing compound and then reacting the resultant intermediate with water. The compounds have heretofore undiscovered antimicrobial and antihypertensive properties.
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