- Synthesis of a novel cyclic prodrug of S -allyl-glutathione able to attenuate LPS-induced ROS production through the inhibition of MAPK pathways in U937 cells
-
A novel cyclic prodrug of S-allyl-glutathione (CP11), obtained by using an acyloxy-alkoxy linker, was estimated for its pharmacokinetic and biological properties. The stability of CP11 was evaluated at pH 1.2, 7.4, in simulated fluids with different concentrations of enzymes, and in human plasma. The anti-inflammatory ability of CP11 was assessed in U937 cells, an immortalized human monocyte cell line. Results showed that CP11 is stable at acidic pH showing a possible advantage for oral delivery due to the longer permanence in the stomach. Having a permeability coefficient of 2.49 × 10-6 cm s-1, it was classified as discrete BBB-permeable compound. Biological studies revealed that CP11 is able to modulate inflammation mediated by LPS in U937 cells preventing the increase of ROS intracellular levels through interaction with the MAPK pathway.
- Patruno, Antonia,Fornasari, Erika,Di Stefano, Antonio,Cerasa, Laura S.,Marinelli, Lisa,Baldassarre, Leonardo,Sozio, Piera,Turkez, Hasan,Franceschelli, Sara,Ferrone, Alessio,Di Giacomo, Viviana,Speranza, Lorenza,Felaco, Mario,Cacciatore, Ivana
-
-
Read Online
- PRIMARY AMINE COMPOUND OR SECONDARY AMINE COMPOUND-ACIDIC POLYSACCHARIDE CONJUGATE AND PRODUCTION METHOD THEREFOR
-
Provided is a novel conjugate of a primary or secondary amine compound with an acidic polysaccharide, which is a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, where in Formula (I), D, R1, R2, A, a
- -
-
-
- Macrocyclic prodrugs of a selective nonpeptidic direct thrombin inhibitor display high permeability, efficient bioconversion but low bioavailability
-
The only oral direct thrombin inhibitors that have reached the market, ximelagatran and dabigatran etexilat, are double prodrugs with low bioavailability in humans. We have evaluated an alternative strategy: the preparation of a nonpeptidic, polar direct
- Andersson, Vincent,Bergstr?m, Fredrik,Br?nalt, Jonas,Gr?nberg, Gunnar,Gustafsson, David,Karlsson, Staffan,Polla, Magnus,Bergman, Joakim,Kihlberg, Jan
-
p. 6658 - 6670
(2016/08/05)
-
- THERAPEUTIC COMPOUNDS AND COMPOSITIONS
-
The present invention provides compounds and compositions that inhibit Factor XIa or kallikrein and methods of using these compounds and composition.
- -
-
Paragraph 0487
(2015/09/22)
-
- (3S,11aR)-6-[(phenylmethyl)oxy]-3-methyl-2,3,11,11a-tetrahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-5,7-dione of the formula P-9 and/or (3S,11aR)-6-[(phenymethyl)oxy]-8-bromo-3-methyl-2,3,11,11a-tetrahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-5,7-dione of the formula P-10
-
The compounds are intermediates in the preparation of therapeutic agents useful in the treatment of viral infections, particularly HIV infection. The compounds are (3S,11aR)-6-[(phenylmethyl)oxy]-3-methyl-2,3,11,11a-tetrahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-5,7-dione of the formula P-9 and/or (3S,11aR)-6-[(phenylmethyl)oxy]-8-bromo-3-methyl-2,3,11,11a-tetrahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-5,7-dione of the formula P-10.
- -
-
Page/Page column 30
(2016/01/20)
-
- Pharmaceutical composition for the treatment or prevention of stroke and systemic embolism
-
The present invention relates to a prodrug useful for treating or preventing a stroke and systemic embolism and suitable for being effectively used in the oral delivery of dabigatran, and to a compound represented by chemical formula 1, a pharmaceutically acceptable salt thereof, and a hydrate thereof or a solvate thereof. The compound represented by the chemical formula 1, the pharmaceutically acceptable salt thereof, and the hydrate thereof or the solvate thereof are useful for treating or preventing a stroke and systemic embolism, and is suitable for being effectively used in oral delivery since the absorption rate, that is, bioavailability of dabigatran is improved.(AA) DSC curve of dabigatran pivoxyl (+)-(1S)- campo-10-sulfonateCOPYRIGHT KIPO 2015
- -
-
Paragraph 0306; 0312-0315
(2016/11/17)
-
- PROSTAGLANDIN-BISPHOSPHONATE CONJUGATE COMPOUNDS, METHODS OF MAKING SAME, AND USES THEREOF
-
The invention provides, in part, amino-bisphosphonate-prostaglandin conjugate compounds as well as methods for their synthesis. Said compounds may be used as EP4 agonist compounds in the prevention or treatment of conditions associated with abnormal or excessive bone loss, with abnormal or reduced bone resorption, or with abnormal calcium metabolism.
- -
-
Page/Page column 41
(2011/12/14)
-
- Azidomethyl 4-nitrophenyl carbonate-A reagent for the one-step introduction of the azidomethyloxycarbonyl (Azoc) protecting group
-
Presented here is the three-step synthesis of azidomethyl 4-nitrophenyl carbonate in 58% overall yield. This carbonate allows for the high-yielding (≥90%) introduction of the phosphine-labile azidomethyloxycarbonyl (Azoc) protecting group in one step. The reagent protects a range of amines, including amino acids. For nonionic substrates, pure carbamates are obtained after extractive workup. Georg Thieme Verlag Stuttgart - New York.
- Kaiser, Andreas,Richert, Clemens
-
scheme or table
p. 2267 - 2270
(2010/11/03)
-
- CHEMICAL COMPOUNDS
-
The present invention features compounds that are prodrugs of HIV integrase inhibitors and therefore are useful in the inhibition of HIV replication, the prevention and/or treatment of infection by HIV, and in the treatment of AIDS and/or ARC.
- -
-
Page/Page column 25-26
(2010/04/03)
-
- COMPOUNDS AND USES THEREOF
-
This invention relates to novel compounds having the structural Formula (I) below: and their pharmaceutically acceptable salts or tautomers, compositions and methods of use thereof. These novel compounds provide a treatment or prophylaxis of at least one symptom or condition associated with schizophrenia and other psychotic disorders, dementia and other cognitive disorders, anxiety disorders, mood disorders, sleep disorders, disorders usually first diagnosed in infancy, childhood, or adolescence and neurodegenerative disorders.
- -
-
Page/Page column 39-40
(2008/12/07)
-
- Design, synthesis, and evaluation of novel mutual prodrugs (hybrid drugs) of all-trans-retinoic acid and histone deacetylase inhibitors with enhanced anticancer activities in breast and prostate cancer cells in vitro
-
Novel mutual prodrugs (MPs) of ATRA (all-trans-retinoic acid) and HDIs (histone deacetylase inhibitors) (10, 13, 17-19) connected via glycine acyloxyalkyl carbamate linker (AC linker) or through a benzyl ester linker (1,6-elimination linker) were rationally designed and synthesized. Most of our novel MPs were potent inhibitors of growth of several hormone-insensitive/drug resistant breast cancer cell lines and the hormone-insensitive PC-3 prostate cancer cell line. The novel MPs exhibited differential antiproliferative potencies in both MDA-MB-231 and PC-3 cell lines. Whereas 19 (VNLG/124) [4-(butanoyloxymethyl)phenyl(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6, 6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoate] with a GI50 of 10 nM was the most potent MP versus the MDA-MB-231 cells, 13 (VNLG/66) [{N-[N-{2-[4-{[3-pyridylmethoxy)carbonyamino]-methyl}phenyl)carbonylamino] phenyl} carbamoylcarbamoyloxy}methyl(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6- trimethyl cyclohex-1-enyl)nona-2,4,6,8-tetraenoate] with a GI50 = 40 nM was the most potent versus the PC-3 cells. MP 19 exhibited the most benefit because its GI50 of 10 nM versus MDA-MB-231 cells was remarkably 1085-fold lower than that of parent ATRA and over 100000-fold lower than butyric acid (BA).
- Gediya, Lalji K.,Khandelwal, Aakanksha,Patel, Jyoti,Belosay, Aashvini,Sabnis, Gauri,Mehta, Jhalak,Purushottamachar, Puranik,Njar, Vincent C. O.
-
experimental part
p. 3895 - 3904
(2009/05/07)
-
- MUTUAL PRODRUGS AND METHODS TO TREAT CANCER
-
Mutual prodrugs comprising retinoids and histone deacetylase inhibitors, methods for production of the mutual prodnigs, and methods of treatment comprising administration of the mutual prodrugs. The retinoids include all-trans retinoic acid, 13-cis retinoic acid, and retinoic acid analogs that have a substitution at C-4. Further, the mutual prodrugs of the present invention can be used as therapeutic agents for the treatment of cancer and dermatological diseases and conditions. Pharmaceutical compositions comprising the mutual prodrugs.
- -
-
Page/Page column 38; 43
(2009/01/24)
-
- Prodrugs of GABA analogs, compositions and uses thereof
-
The present invention provides prodrugs of GABA analogs, pharmaceutical compositions of prodrugs of GABA analogs and methods for making prodrugs of GABA analogs. The present invention also provides methods for using prodrugs of GABA analogs and methods for using pharmaceutical compositions of prodrugs of GABA analogs for treating or preventing common diseases and/or disorders.
- -
-
Page/Page column 36
(2010/11/24)
-
- Prodrugs of GABA analogs, compositions and uses thereof
-
The present invention provides prodrugs of GABA analogs, pharmaceutical compositions of prodrugs of GABA analogs and methods for making prodrugs of GABA analogs. The present invention also provides methods for using prodrugs of GABA analogs and methods for using pharmaceutical compositions of prodrugs of GABA analogs for treating or preventing common diseases and/or disorders.
- -
-
-
- 5-AMIDINO-2-HYDROXYBENZENESULFONAMIDE DERIVATIVES, MEDICINAL COMPOSITIONS CONTAINING THE SAME, MEDICINAL USE THEREOF AND INTERMEDIATES IN THE PRODUCTION THEREOF
-
The present invention relates to a 5-amidino-2-hydroxybenzenesulfonamide derivative represented by the general formula: wherein R1 is an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted lower alkenyl group, a cycloalkyl group or a lower acyl group etc.; Q is a hydrogen atom or an optionally substituted lower alkyl group; and Z is a hydrogen atom or a hydroxy group etc., or a pharmaceutically acceptable salt thereof, which exert a potent and selective activated blood coagulation factor X inhibitory activity and is useful as an agent for the prevention or treatment of a disease occurred associating an activated blood coagulation factor X, a pharmaceutical composition comprising the same and an intermediate thereof. These compounds are useful as preventives or remedies for various diseases such as brain infarction, cerebral thrombosis, cerebral embolism, TIA, cerebral vascular jerk, Alzheimer's diseases, myocardial infarction, heart attack, heart failure, thrombosis, pulmonary infarction and pulmonary embolism.
- -
-
-
- Synthesis of a novel cyclic prodrug of RGD peptidomimetic to improve its cell membrane permeation
-
The objective of this work was to synthesize cyclic prodrug 2 derived from the parent RGD peptidomimetic 1 and to evaluate its chemical and enzymatic stabilities and antithrombic activity. Cyclic prodrug 2 was formed to improve the cell membrane permeation of RGD peptidomimetic 1 by transiently masking the unfavorable physicochemical properties of compound 1. Cyclic prodrug 2 was synthesized by linking the amino and carboxylic acid groups of parent 1 via the (acyloxy)alkoxy promoiety. The prodrug-to-drug conversion of cyclic prodrug 2 was evaluated in isolated esterase and human plasma in the absence and presence of the esterase inhibitor paraoxon. The rate of hydrolysis of cyclic prodrug 2 was significantly faster in plasma (t1/2 = 33.5 ± 0.6 min) than in PBS (t1/2 = 314 ± 11 min). Cyclic prodrug 2 was converted by esterase to the parent compound 1 and this conversion was inhibited by an esterase inhibitor, paraoxon. The IC50 (4 μM) of cyclic prodrug 2 was higher than the IC50 (1.9 μM) of parent drug 1. The antithrombic activity of cyclic prodrug 2 depends on the incubation time in platelet-rich plasma; the activity increases with incubation time, suggesting that the prodrug-to-drug conversion is time-dependent and mediated by esterase. Cyclic prodrug 2 was more stable under acidic and neutral conditions than under basic conditions, suggesting that handling and formulation of this prodrug should be undertaken under acidic conditions.
- Song, Xiaoping,Xu, Christine R.,He, Henry T.,Siahaan, Teruna J.
-
p. 285 - 301
(2007/10/03)
-
- Acyclic and cyclic guanidine-and acetamidine derivatives, their preparation and their use as pesticides, esp. as parasiticides
-
Novel pesticides of formula (I) wherein the substituents R, R1, R2, R2′, T, U, X and Y are as defined in claim 1, are described. Also described are compositions suitable for use as parasiticides comprising those compounds
- -
-
-
- N-acylamino acid amide compounds and intermediates for preparation thereof
-
The present invention discloses the compound represented by the formula (I): wherein A represents the following formula (a-1) or the following formula (a-2): B represents the following formula (b): (wherein the symbols are each as defined in the specification) or a pharmaceutically acceptable salts thereof, and intermediates for the preparation thereof, which have excellent platelet aggregation inhibitory activity and other properties and useful as prophylactic or therapeutic agents for diseases associated with a fibrinogen receptor, thrombosis, infarction and the like.
- -
-
-
- Synthesis of a novel esterase-sensitive cyclic prodrug of a hexapeptide using an (acyloxy)alkoxy promoiety
-
Synthetic methodology for preparing novel esterase-sensitive cyclic prodrugs of peptides with increased protease stability and cell membrane permeability compared to linear peptides is described. Cyclic prodrug 1 of the hexapeptide H-Trp-Ala-Gly-Gly-Asp-Ala-OH linked by the N-terminal amino group to the C-terminal carboxyl group via an (acyloxy)alkoxy promoiety was synthesized. A convergent synthetic approach involving Boc[[(alaninyloxy)methyl]carbonyl]-N-tryptophan (2) and H-Ala-Gly-Gly-Asp(OBzl)-OTce (3) was used. The key fragment 2 has the promoiety inserted between the Ala and the Trp residues. Fragment 3 was synthesized by a solution-phase approach using standard Boc-amino acid chemistry. These fragments were coupled to produce the protected linear hexapeptide, which after deprotection was cyclized using standard high-dilution techniques to yield cyclic prodrug 1. In pH 7.4 buffer (HBSS) at 37°C, cyclic prodrug 1 was shown to degrade quantitatively to the hexapeptide (t( 1/4 ) = 206 ± 11 min). The rate of hydrolysis of cyclic prodrug 1 was significantly faster in human blood (t( 1/4 ) = 132 ± 4 min) than in HBSS. Paraoxon, a known inhibitor of esterases, slowed this hydrolysis of cyclic prodrug 1 to a value (t( 1/4 ) = 198 ± 9 min) comparable to the chemical stability. In human blood, cyclic prodrug 1 was shown to be 25-fold more stable than the linear hexapeptide.
- Gangwar, Sanjeev,Pauletti, Giovanni M.,Siahaan, Teruna J.,Stella, Valentino J.,Borchardt, Ronald T.
-
p. 1356 - 1362
(2007/10/03)
-
- Process for preparing novel N-(acyloxy-alkoxy)carbonyl derivatives useful as bioreversible prodrug moieties for primary and secondary amine functions in drugs
-
This invention relates to a new one-step process for preparation of novel N-(acyloxyalkoxy)carbonyl derivatives useful as bioreversible prodrug moieties for drugs having a primary or secondary amine function thereon.
- -
-
-
- (Acyloxy)alkyl Carbamates as Novel Bioreversible Prodrugs for Amines: Increased Permeation through Biological Membranes
-
(Acyloxy)alkyl carbamates of the type R1R2N-CO-O-CHR3-OCO-R4 are described as novel bioreversible prodrugs for primary and secondary amines.These were prepared either by a one-step reaction involving nucleophilic attack on p-nitrophenyl α-(acyloxy)alkyl carbonates with displacement of p-nitrophenol or by reaction of α-haloalkyl carbamates with silver or mercury salts of carboxylic acids.Enzymatic hydrolysis of the ester bond in these ester carbamates leads to a cascade reaction resulting in rapid regeneration of the parent amine.Permeability measurements of such nonionic derivatives of atenolol, betaxolol, pindolol, propranolol, and timolol through fuzzy rat skin and rabbit cornea mounted on diffusion cells show that derivatization of the hydrophilic β-blockers results in several-fold increase in permeation through these biological membranes.However, prodrug modification of the lipophilic β-blockers leads to little advantage in permeability characteristics.
- Alexander, Jose,Cargill, Robyn,Michelson, Stuart R.,Schwam, Harvey
-
p. 318 - 322
(2007/10/02)
-