- PGDH INHIBITORS AND METHODS OF MAKING AND USING
-
Disclosed herein are compounds that can inhibit 15-hydroxyprostaglandin dehydrogenase. Such compounds may be administered to subjects that may benefit from modulation of prostaglandin levels.
- -
-
Paragraph 0271; 0273; 0362-0363
(2021/07/31)
-
- Dual Farnesoid X Receptor/Soluble Epoxide Hydrolase Modulators Derived from Zafirlukast
-
The nuclear farnesoid X receptor (FXR) and the enzyme soluble epoxide hydrolase (sEH) are validated molecular targets to treat metabolic disorders such as non-alcoholic steatohepatitis (NASH). Their simultaneous modulation in vivo has demonstrated a triad of anti-NASH effects and thus may generate synergistic efficacy. Here we report dual FXR activators/sEH inhibitors derived from the anti-asthma drug Zafirlukast. Systematic structural optimization of the scaffold has produced favorable dual potency on FXR and sEH while depleting the original cysteinyl leukotriene receptor antagonism of the lead drug. The resulting polypharmacological activity profile holds promise in the treatment of liver-related metabolic diseases.
- Schierle, Simone,Helmst?dter, Moritz,Schmidt, Jurema,Hartmann, Markus,Horz, Maximiliane,Kaiser, Astrid,Weizel, Lilia,Heitel, Pascal,Proschak, Anna,Hernandez-Olmos, Victor,Proschak, Ewgenij,Merk, Daniel
-
-
- Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1
-
Histone modifying proteins, specifically histone deacetylases (HDACs) and bromodomains, have emerged as novel promising targets for anticancer therapy. In the current work, based on available crystal structures and docking studies, we designed dual inhibitors of both HDAC6/8 and the bromodomain and PHD finger containing protein 1 (BRPF1). Biochemical and biophysical tests showed that compounds 23a,b and 37 are nanomolar inhibitors of both target proteins. Detailed structure-activity relationships were deduced for the synthesized inhibitors which were supported by extensive docking and molecular dynamics studies. Cellular testing in acute myeloid leukemia (AML) cells showed only a weak effect, most probably because of the poor permeability of the inhibitors. We also aimed to analyse the target engagement and the cellular activity of the novel inhibitors by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines.
- Erdmann, Frank,Günther, Stefan,Ghazy, Ehab,Hügle, Martin,Herp, Daniel,Jung, Manfred,Morales, Elizabeth R.,Robaa, Dina,Romier, Christophe,Schmidt, Matthias,Schmidtkunz, Karin,Sippl, Wolfgang,Zeyen, Patrik
-
supporting information
(2020/06/03)
-
- Boosting Anti-Inflammatory Potency of Zafirlukast by Designed Polypharmacology
-
Multitarget design offers access to bioactive small molecules with potentially superior efficacy and safety. Particularly multifactorial chronic inflammatory diseases demand multiple pharmacological interventions for stable treatment. By minor structural changes, we have developed a close analogue of the cysteinyl-leukotriene receptor antagonist zafirlukast that simultaneously inhibits soluble epoxide hydrolase and activates peroxisome proliferator-activated receptor γ. The triple modulator exhibits robust anti-inflammatory activity in vivo and highlights the therapeutic potential of designed multitarget agents.
- Schierle, Simone,Flauaus, Cathrin,Heitel, Pascal,Willems, Sabine,Schmidt, Jurema,Kaiser, Astrid,Weizel, Lilia,Goebel, Tamara,Kahnt, Astrid S.,Geisslinger, Gerd,Steinhilber, Dieter,Wurglics, Mario,Rovati, G. Enrico,Schmidtko, Achim,Proschak, Ewgenij,Merk, Daniel
-
supporting information
p. 5758 - 5764
(2018/06/18)
-
- COMPOUNDS AND COMPOSITIONS AS TOLL-LIKE RECEPTOR 7 AGONISTS
-
The invention provides compounds of formula (I), immunogenic compositions and pharmaceutical compositions comprising such compounds and methods of using such compounds to treat diseases or disorders associated with Toll-Like Receptor 7 activity.
- -
-
Paragraph 48
(2015/11/24)
-
- Mild Benzylic Monobromination of Methyl Toluates in Aqueous CTAB
-
A strategy has been developed for the regioselective monobromination of methyl toluates by using tert-butylhydrogen peroxide and potassium bromide (TBHP/KBr) in a cetyltrimethylammonium bromide (CTAB) micellar medium. Ultrasonic and microwave-assisted protocols recorded increased rates and product yields under mild reaction conditions, coupled with a straightforward isolation procedure.
- Reddy, Kancharla Rajendar,Rajanna, Kamatala C.,Venkateswarlu, Marri,Saiprakash
-
p. 2485 - 2487
(2015/07/27)
-
- CHROMONE INHIBITORS OF S-NITROSOGLUTATHIONE REDUCTASE
-
The present invention is directed to inhibitors of S-nitrosoglutathione reductase (GSNOR), pharmaceutical compositions comprising such GSNOR inhibitors, and methods of making and using the same.
- -
-
Page/Page column 44
(2011/09/15)
-
- An improved and scalable process for zafirlukast: An asthma drug
-
An improved and scalable process for the large-scale production of zafirlukast (Accolate), an important drug for asthma, is discussed along with impurity and scale-up-related issues.
- Goverdhan, Gilla,Reddy, Anumula Raghupathi,Sampath, Aalla,Srinivas, Kurella,Himabindu, Vurimidi,Reddy, Ghanta Mahesh
-
experimental part
p. 67 - 72
(2010/04/22)
-
- TROPANE COMPOUNDS
-
A compound according to Formula I or II: (I) or (II) wherein R1, R1b, R2, L1, and L2 and L2b are as defined in the specification, pharmaceutical compositions thereof, and methods of use thereof.
- -
-
Page/Page column 391-392
(2009/05/30)
-
- SUBSTITUTED INDOLES
-
Disclosed herein are substituted indole cysteinyl leukotriene receptor modulators of Formula I, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.
- -
-
Page/Page column 51
(2009/08/14)
-
- THIAZOLE AND OXAZOLE KINASE INHIBITORS
-
The present invention provides thiazole and oxazole compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.
- -
-
Page/Page column 179-180
(2009/04/25)
-
- PROCESSES FOR PREPARING ZAFIRLUKAST
-
An improved process for the preparation of substantially pure zafirlukast and pharmaceutical compositions thereof.
- -
-
Page/Page column 8
(2009/06/27)
-
- FUSED QUINOLINE DERIVATIVE AND USE THEREOF
-
The present invention aims at provision of a quinoline derivative having a neurokinin 2 (NK2) receptor antagonistic action and relates to a compound represented by the formula (I) wherein Rl is a hydrogen atom and the like; R2 is a hydrogen atom, a hydrocarbon group optionally having substituent(s) and the like; R3 is unsubstituted (i.e., absence), a hydrogen atom and the like; R4 and R5 are the same or different and each is a hydrogen atom, a hydrocarbon group optionally having substituent(s), and the like; R6is (cyclic group optionally having substituent(s)) -carbonyl, and the like; R7, R8,R9 and R10 are the same or different and each is a hydrogen atom, halogen and the like; or R7and R8,R8 and R9,and R9 and R10 may form a ring together with the adjacent carbon atoms; n is an integer of 1 to 5; --- represents unsubstituted (i.e., absence) or a single bond; and --- represents a single bond or a double bond, or a salt thereof, and the like.
- -
-
Page/Page column 120-121
(2008/06/13)
-
- Thrombin inhibitors
-
This application relates to novel compounds of formula I (and their pharmaceutically acceptable salts), as defined herein, processes and intermediates for their preparation, pharmaceutical formulations comprising the novel compounds of formula I, and the use of defined compounds of formula I as thrombin inhibitors.
- -
-
-
- Antithrombotic agents
-
This application relates to novel compounds of formula I (and their pharmaceutically acceptable salts), as defined herein, processes and intermediates for their preparation, pharmaceutical formulations comprising the novel compounds of formula I, and the use of the compounds of formula I as thrombin inhibitors.
- -
-
-
- Antithrombotic Agents
-
This application relates to novel compounds of formula (I) (and their pharmaceutically acceptable salts), as defined herein, processes and intermediates for their preparation, pharmaceutical formulations comprising the novel compounds of formula (I), and the use of the compounds of formula (I) as thrombin inhibitors.
- -
-
-
- Synthesis and pharmacological evaluation of new cysLT1 receptor antagonists
-
This paper describes the synthesis and pharmacological evaluation of three series of compounds 4a-b, 13a-k and 19, structurally related to the known potent cysLT1 receptor antagonists RG-12553, IC1-204219 and ONO-1078, respectively. The common structural feature of these new series is the presence of a 4-quinolone nucleus acting as a template for substitution of the aromatic nucleus present in the prototype antagonists. We describe the evolution of these series leading to antagonists with potency at nanomolar concentrations in vitro.
- Griera,Armengol,Reyes,Alvarez,Palomer,Cabre,Pascual,Garcia,Mauleon
-
p. 547 - 570
(2007/10/03)
-
- Bicyclic carbamates and methods of treating inflammatory diseases using the same
-
A compound of the formula STR1 wherein R is defined herein is useful as an anti-inflammatory agent.
- -
-
-
- Heter-aliphatic carboxamides
-
This invention provides a series of novel heter-aliphatic carboxamides of formula I in which the group >Z--Y--XC=CH--NN--CH=CC=N--NN--N=C and the other radicals have the meanings defined in the following specification. The compounds of formula I are leukotriene antagonists. The invention also provides pharmaceutically acceptable salts of the formula I compounds; pharmaceutical compositions containing the formula I compound, or their salts, for use in the treatment of, for example, allergic or inflammatory diseases, or endotoxic or traumatic shock conditions; and processes for the manufacture of the formula I compounds, as well as intermediates for use in such manufacture.
- -
-
-
- Cyclic amides as medicaments
-
This invention provides a series of novel cyclic amides of formula I in which the group >Z--Y--XC=CH--NN-CH=CHC=N--NN--N=C and the other radicals have the meanings defined in the following specification. The compounds of formula I are leukotriene antagonists. The invention also provides pharmaceutically acceptable salts of the formula I compounds; pharmaceutical compositions containing the formula I compound, or their salts, for use in the treatment of, for example, allergic or inflammatory diseases, or endotoxic or traumatic shock conditions; and processs for the manufacture of the formula I compounds, as well as intermediates for use in such manufacture.
- -
-
-
- Evolution of a Series of Peptidoleukotriene Antagonists: Synthesis and Structure-Activity Relationships of 1,6-Disubstituted Indoles and Indazoles
-
A perception of structural similarities between two independent series of leukotriene antagonists (one emanating from FPL 55712 and one based upon the leukotrienes themselves) led to the discovery of a novel class of indole and indazole derived antagonists of peptidoleukotrienes.A systematic exploration of C-6 substituted 4-(indol-1-ylmethyl)-3-methoxybenzoic acids identified cyclopentylacetamide and cyclopentylurethane as preferred substituents.The corresponding indazoles were equipotent.These compounds are selective leukotriene antagonists with pKB values of 7.5-7.8 vs LTE4 on guinea pig trachea.
- Brown, Frederick J.,Yee, Ying K.,Cronk, Laura A.,Hebbel, Kevin C.,Krell, Robert D.,Snyder, David W.
-
p. 1771 - 1781
(2007/10/02)
-
- Aliphatic carboxamides
-
This invention provides a series of novel heterocyclic aliphatic carboxamides of formula I in which the group >Z--Y--XC=CH--NN--CH=CC=N--NN--N=C and the other radicals have the meanings defined in the following specification. The compounds of formula I are leukotriene antagonists. The invention also provides pharmaceutically acceptable salts of the formula I compounds; pharmaceutical compositions containing the formula I compound, or their salts, for use in the treatment of, for example, allergic or inflammatory diseases, or endotoxic or traumatic shock conditions; and processes for the manufacture of the formula I compounds, as well as intermediates for use in such manufacture.
- -
-
-
- Indole and indazole keto sulphones as leukotriene antagonists
-
This invention provides a series of novel keto sulfones of formula I STR1 in which the group =A-- is selected from =C(Ra)-- and =N-- and the other radicals have the meanings defined in the following specification. The compounds of formula I are leukotriene antagonists. The invention also provides pharmaceutically acceptable salts of the formula I compounds; pharmaceutical compositions containing the formula I compound, or their salts, for use in the treatment of, for example, allergic or inflammatory diseases, or endotoxic or traumatic shock conditions; and processes for the manufacture of the formula I compounds, as well as intermediates for use in such manufacture.
- -
-
-
- Heterocyclic amide derivatives and pharmaceutical use
-
The invention concerns novel, pharmaceutically useful, amide derivatives of certain benzoheterocyclylalkanoic acids (and related tetrazoles and acylsulphonamides) of the formula I and salts thereof, wherein the radicals R1, R2, L, X, Y, Z, A1, Q, A2 and M have the meanings set out in the specification. The invention also includes pharmaceutical compositions incorporating a formula I compound or a salt thereof, a process for the manufacture of the said compound, together with intermediates for use in the latter process. STR1
- -
-
-
- Synthesis and pharmacological characterization of a series of leukotriene analogues with antagonist and agonist activities
-
The synthesis and biological characterization of a series of novel leukotriene antagonists and agonists are reported. All of these compounds are derivatives of (5S,6R,7Z)-5-hydroxy-6-mercapto-9-phenyl-7-nonenoic acid. One of the more potent compounds is (5S,6R,7Z)-6-[[(4-carboxy-2-methoxyphenyl)methyl]thio]-5-hydroxy -9-(4-heptylphenyl)-7-nonenoic acid (3f). In vitro evaluation of this compound on guinea pig trachea revealed that it is a competitive antagonist of LTD4 and LTE4 with pK(B) values of 6.4 and 5.8, respectively. On guinea pig ileum, the pK(B) values obtained for it with LTD4 and E4 were both 7.2. The selectivity of 3f was shown by its lack of effect on carbachol, histamine, and barium chloride concentration-response curves in guinea pig trachea.
- Bernstein,Vacek,Adams,Snyder,Krell
-
p. 692 - 696
(2007/10/02)
-
