- Discovery of a tricyclic farnesoid X receptor agonist HEC96719, a clinical candidate for treatment of non-alcoholic steatohepatitis
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Non-alcoholic fatty liver disease (NAFLD) is becoming the most predominant burden of chronic liver disease worldwide. Non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD, can develop into cirrhosis and hepatocellular cancer. Unfortunately, current options for therapeutic treatment of NASH are very limited. Among multiple pathways in NASH, farnesoid X receptor (FXR), a nuclear bile acid receptor, is well-recognized as an important effective target. Here we report the synthesis and characterization of compound HEC96719 a novel tricyclic FXR agonist based on a prior high-affinity nonsteroidal molecule GW4064. HEC96719 exhibits excellent potency superior to GW4064 and obeticholic acid in in vitro and in vivo assays of FXR activation. It also shows higher FXR selectivity and more favorable tissue distribution dominantly in liver and intestine. Preclinical data on pharmacokinetic properties, efficacy, and safety profiles overall indicate that HEC96719 is a promising drug candidate for NASH treatment.
- Cao, Shengtian,Yang, Xinye,Zhang, Zheng,Wu, Junwen,Chi, Bo,Chen, Hong,Yu, Jianghong,Feng, Shanshan,Xu, Yulin,Li, Jing,Zhang, Yingjun,Wang, Xiaojun,Wang, Yan
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supporting information
(2022/01/24)
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- Cross-coupling strategy for the synthesis of diazocines
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Ethylene bridged azobenzenes are novel, promising molecular switches that are thermodynamically more stable in the (Z) than in the (E) configuration, contrary to the linear azobenzene. However, their previous synthetic routes were often not general, and yields were poorly reproducible, and sometimes very low. Here we present a new synthetic strategy that is both versatile and reliable. Starting from widely available 2-bromobenzyl bromides, the designated molecules can be obtained in three simple steps.
- Eleya, Nadi,Li, Shuo,Staubitz, Anne
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supporting information
p. 1624 - 1627
(2020/03/13)
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- Annulated bacteriochlorins for near-infrared photophysical studies
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Molecules with strong absorption in the near-infrared (NIR) spectral region are of interest for a variety of applications in the photosciences. Nature's NIR absorbers are bacteriochlorophylls, which contain a tetrahydroporphyrin chromophore accentuated by
- Fujita, Hikaru,Jing, Haoyu,Krayer, Michael,Allu, Srinivasarao,Veeraraghavaiah, Gorre,Wu, Zhiyuan,Jiang, Jianbing,Diers, James R.,Magdaong, Nikki Cecil M.,Mandal, Amit K.,Roy, Arpita,Niedzwiedzki, Dariusz M.,Kirmaier, Christine,Bocian, David F.,Holten, Dewey,Lindsey, Jonathan S.
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supporting information
p. 7209 - 7232
(2019/05/24)
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- GLUCOSE-SENSITIVE ALBUMIN-BINDING DERIVATIVES
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This invention relates to glucose-sensitive albumin-binding diboron conjugates. More particularly the invention provides novel diboron compounds, and in particular diboronate or diboroxole compounds, useful as intermediate compounds for the synthesis of diboron conjugates. The diboron compounds are characterized by formula (I), which is: R1-X-R2, and wherein "X" is a mono- to multiatomic linker and where R1 and R2, which may be identical or different, each represents a group of Formula (lla) or (IIb) Also described are diboron conjugates represented by the general Formula (I'), which is: R1'-X'-R2', in which either the moeities R1' or R2' or X' carry a drug that is covalently attached to the diboron compound.
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Page/Page column 151; 152; 153
(2019/05/30)
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- A Four-Step Synthesis of (±)-γ-Lycorane via Pd0-Catalyzed Double C(sp2)-H/C(sp3)-H Arylation
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An expedient synthesis of lycorine alkaloids is reported using a palladium(0)-catalyzed double C-X/C-H arylation as the key step. The selectivity of this reaction was controlled through the judicious choice of the two halogen atoms, and its generality was
- Rocaboy, Ronan,Dailler, David,Baudoin, Olivier
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supporting information
p. 772 - 775
(2018/02/09)
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- PHTHALAZINE DERIVATIVES, AND PREPARATION METHOD, PHARMACEUTICAL COMPOSITION AND USE THEREOF
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The present invention provides a compound of formula I, a cis-trans isomer, an enantiomer, a diastereoisomer, a racemate, a solvate, a hydrate, or a pharmaceutical acceptable salt and ester thereof, a preparation method for preparing the same, a pharmaceutical composition comprising the same and a use of the compound as an α5-GABAA receptor regulator, wherein T, Z, A and Y are as defined in the description.
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Paragraph 0199
(2018/11/21)
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- HETEROCYCLIC COMPOUNDS AS RSV INHIBITORS
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The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, esters, or prodrugs thereof: Formula (I) which inhibit Respiratory Syncytial Virus (RSV). The present invention further relates to pharmaceutical compositions
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Page/Page column 150-151
(2017/08/07)
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- 3-PHOSPHOGLYCERATE DEHYDROGENASE INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 00538-00540
(2017/10/06)
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- 3-ALKYL-4-AMIDO-BICYCLIC [4,5,0] HYDROXAMIC ACIDS AS HDAC INHIBITORS
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The present disclosure relates to inhibitors of zinc-dependent histone deacetylases (HDACs) useful in the treatment of diseases or disorders associated with an HDAC, e.g., HDAC6, having a Formula I: where R, L, X1, X2, X3, X4, Y1, Y2, Y3, and Y4 are described herein.
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Paragraph 0591-0592
(2016/08/29)
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- PIPERIDINE DERIVATIVES AND METHODS OF TREATING HEPATITIS B INFECTIONS
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Provided herein are compounds useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject.
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Paragraph 0269; 0270; 0271
(2015/12/12)
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- AZEPANE DERIVATIVES AND METHODS OF TREATING HEPATITIS B INFECTIONS
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Provided herein are compounds useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject.
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Paragraph 0804; 0805; 0806
(2015/07/22)
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- AZEPANE DERIVATIVES AND METHODS OF TREATING HEPATITIS B INFECTIONS
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Provided herein are compounds useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject.
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Paragraph 0801
(2015/09/22)
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- SUBSTITUTED TRICYCLIC COMPOUNDS WITH ACTIVITY TOWARDS EP1 RECEPTORS
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The present invention belongs to the field of EP1 receptor ligands. More specifically it refers to compounds of general formula (I) having great affinity and selectivity for the EP1 receptor. The invention also refers to the process for their preparation, to their use as medicament for the treatment and/or prophylaxis of diseases or disorders mediated by the EP1 receptor as well as to pharmaceutical compositions comprising them.
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Page/Page column 49-50
(2013/10/22)
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- 3-[2-(Aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phenyl] benzoates as soft ROCK inhibitors
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Clinical development of ROCK inhibitors has so far been limited by systemic or local ROCK-associated side effects. A soft drug approach, which involves predictable metabolic inactivation of an active compound to a nontoxic metabolite, could represent an a
- Boland, Sandro,Defert, Olivier,Alen, Jo,Bourin, Arnaud,Castermans, Karolien,Kindt, Nele,Boumans, Nicki,Panitti, Laura,Van De Velde, Sarah,Stalmans, Ingeborg,Leysen, Dirk
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supporting information
p. 6442 - 6446
(2013/11/19)
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- COMPOUND HAVING SPIRO-BONDED CYCLIC GROUP AND USE THEREOF
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The invention relates to a compound represented by formula (I): a salt thereof, an N-oxide thereof, or a solvate thereof (symbols in the formula are as described in the specification). The compound of the present invention exhibits very low risk of side effects and also has persistent and strong antagonistic activity against CXCR4, and is therefore useful as for example, preventive and/or therapeutic agent for inflammatory and immune diseases, infections (for example, HIV infection), diseases associated with HIV infection (for example, acquired immunodeficiency syndrome (AIDS)), cancer, cancer metastasis, psychoneurotic diseases and cardiovascular diseases (for example, retinopathy), metabolic diseases, cancerous diseases, or an agent for regeneration therapy.
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Page/Page column 45
(2012/05/04)
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- HETEROCYCLIC AMIDES AS ROCK INHIBITORS
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The present invention relates to new kinase inhibitors of formula (I), more specifically ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In particular, the present invention relates to new ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In addition, the invention relates to methods of treatment and use of said compounds in the manufacture of a medicament for the application to a number of therapeutic indications including sexual dysfunction, inflammatory diseases, ophthalmic diseases and Respiratory diseases.
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Page/Page column 70
(2011/10/03)
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- A concise synthesis of 6,7-dihydro-5H-dibenz[c,e]azepin-5-one
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A concise and efficient strategy for the synthesis of dibenz[c,e]azepin-5-ones has been developed. The approach relies on a key transformation involving Suzuki-Miyaura coupling of 2-bromobenzyl azides with 2-(methoxycarbonyl)phenylboronic acid, followed b
- Goh, Young-Hyoung,Kim, Guncheol,Kim, Bum Tae,Heo, Jung-Nyoung
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experimental part
p. 669 - 677
(2010/04/29)
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- Paracyclophanes: Extending the bridges. Synthesis
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Preparatively satisfactory routes to [3.2]paracyclophane (10), [4.2]paracyclophane (14), [4.3]paracyclophane (19) as well as several derivatives of these compounds - among others the bromides 25, the ester 31, the diesters 40-43 - are described using well-established methods of cyclophane chemistry (ring-closure reactions leading to thiacyclophanes, ring contraction by sulfone pyrolysis). The parent systems and their derivatives are now available in gram quantities allowing a study of their chemical properties. Wiley-VCH Verlag GmbH & Co. KGaA, 2009.
- Pechlivanidis, Zissis,Hopf, Henning,Ernst, Ludger
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experimental part
p. 223 - 237
(2009/06/21)
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- A re-examination of the difluoromethylenesulfonic acid group as a phosphotyrosine mimic for PTP1B inhibition
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Protein tyrosine phosphatase 1B (PTP1B) is involved in the down-regulation of insulin signaling and is a well-validated therapeutic target for the treatment of diabetes and obesity. Key to the design of potent inhibitors of PTP1B is a moiety that effectively mimics the phosphate group of the natural phosphotyrosine substrate. Difluoromethylsulfonomethylphenylalanine (F2Smp) is one of the best monoanionic pTyr mimics reported to date. However, the difluoromethylenesulfonic acid (DFMS) group as a phosphate mimic has not been carefully evaluated in the context of a non-peptidyl platform. Here we present a careful examination of the DFMS group as a phosphate mimic. This was achieved by first constructing an analog of a previously reported high affinity, non-peptidyl PTP1B inhibitor (compound 2, IC50 = 8 nM) in which a difluoromethylenephosphonic acid group is replaced with the DFMS moiety (compound 6). We also report the synthesis of its non-fluorinated methylenesulfonic analog (compound 7), as well as two other derivatives in which a distal sulfonamide moiety is replaced with a difluoromethylenesulfonamide group (compounds 8 and 9). Compounds 2 and 6-9 were examined as PTP1B inhibitors. Replacing the distal sulfonamide moiety with a difluoromethylenesulfonamide group had only a modest effect on inhibitor potency. However, compound 6 was approximately a 1000-fold poorer inhibitor than compound 2. Most significantly, inhibition studies with compound 7 and a peptide bearing sulfonomethylphenylalanine revealed that the fluorines have little effect on the potency of the DFMS-bearing inhibitors. This is in contrast to a previous assumption that the fluorines in DFMS-bearing inhibitors contributed significantly to their potency. This may in part explain the large difference in potency between the DFMS and DFMP-bearing compounds. These results also demonstrate that sulfonomethylphenylalanine, a pTyr mimic that is readily constructed, is a relatively good pTyr mimic in comparison to most others that have been reported when examined in the context of the DADE-X-LNH2 peptide platform.
- Hussain, Munawar,Ahmed, Vanessa,Hill, Bryan,Ahmed, Zaheer,Taylor, Scott D.
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p. 6764 - 6777
(2008/12/22)
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- Acyl indoles, compositions containing such compounds and methods of use
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The present invention relates to substituted indoles, compositions containing such compounds and methods of treatment The compounds are glucagon receptor antagonists and thus are useful for treating, preventing or delaying the onset of type 2 diabetes mellitus and related conditions.
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Page/Page column 18
(2008/06/13)
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- 1,2-BIS-(SUBSTITUTED-PHENYL)-2-PROPEN-1-ONES AND PHARMACEUTICAL COMPOSITIONS THEREOF
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The invention relates to compounds, pharmaceutical compositions and methods of using compounds of the general formula (I), or its pharmaceutically acceptable salt or ester, wherein the substituents are defined in the application.
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Page/Page column 126
(2010/02/15)
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- NOVEL BENSOPHENONE DERIVATIVES OR SALTS THEREOF
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A benzophenone derivative represented by the following formula: whereinR1 represents, for example, an optionally substituted heterocyclic group, or a substituted phenyl group; Z represents, for example, an alkylene group; R2 represents, for example, a carboxyl group optionally protected with alkyl;R3 represents, for example, an optionally protected hydroxyl group; R4 represents, for example, an optionally substituted cycloalkyloxy group; and R5 represents, for example, a hydrogen atom, ???or a salt thereof has anti-arthritic activity, inhibits bone destruction caused by arthritis, and provides high safety and excellent pharmacokinetics and thus is useful as therapeutic agent for arthritis. These compounds have inhibitory effect on AP-1 activity and are useful as preventive or therapeutic agent for diseases in which excessive expression of AP-1 is involved.
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Page 119-120
(2010/02/07)
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- Relative rates and approximate rate constants for inter- and intramolecular hydrogen transfer reactions of polymer-bound radicals
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Measurements of relative rates and rate constants for inter- and intramolecular hydrogen transfer reactions of polymer-bound radicals are reported. The relative rate of reaction of resin-bound primary alkyl radical with tributyltin hydride is about 2 times slower than that of the benchmark reaction in solution. The data do not reveal whether this is due to a reduced rate constant or a lower concentration of tin hydride in the resin phase. Yet the difference between solid and solution reactions is small enough to be neglected, and it appears that rate constants measured in solution can be applied directly to resin-bound radicals. A resin-bound aryl radical abstracts a hydrogen atom rapidly (k = 3 x 106 s-1) from its own polymer backbone and linker, and a simplified view of the resin as a "solvent" is suggested for predicting such effects with other polymers and linkers. Rapid cyclizations of resin-bound aryl radicals will be possible, but slower cyclizations and most bimolecular reactions will be difficult due to the competing polymer/linker hydrogen transfer.
- Curran, Dennis P.,Yang, Fanglong,Cheong, Jae-ho
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p. 14993 - 15000
(2007/10/03)
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- Antithrombotic agents
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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.
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Page column 45
(2010/01/31)
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- Diamino benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors. 5. Potency, efficacy, and pharmacokinetic properties of modified C-3 side chain derivatives
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A systematic investigation of the structure-activity relationships of the C-3 side chain of the screening hit la led to the identification of the potent thrombin inhibitors 23c, 28c, and 31c. Their activities (1240, 903, and 1271 x 106 L/mol, respectively) represent 2200- and 2900-fold increases in potency over the starting lead la. This activity enhancement was accomplished with an increase of thrombin selectivity. The in vitro anticoagulant profiles of derivatives 28c and 31c were determined, and they compare favorably with the clinical agent H-R-1-[4aS,- 8aS]perhydroisoquinolyl-prolyl-arginyl aldehyde (D-Piq-Pro-Arg-H; 32). The more potent members of this series have been studied in an arterial/venous shunt (AV shunt) model of thrombosis and were found to be efficacious in reducing clot formation. However, their efficacy is currently limited by their rapid and extensive distribution following administration.
- Sall, Daniel J.,Bailey, Dianna L.,Bastian, Jolie A.,Buben, John A.,Chirgadze, Nickolay Y.,Clemens-Smith, Amy C.,Denney, Michael L.,Fisher, Matthew J.,Giera, Deborah D.,Gifford-Moore, Donetta S.,Harper, Richard W.,Johnson, Lea M.,Klimkowski, Valentine J.,Kohn, Todd J.,Lin, Ho-Shen,McCowan, Jefferson R.,Palkowitz, Alan D.,Richett, Michael E.,Smith, Gerald F.,Snyder, David W.,Takeuchi, Kumiko,Toth, John E.,Zhang, Minsheng
-
p. 649 - 663
(2007/10/03)
-