- Structure-Guided Optimization of HIV Integrase Strand Transfer Inhibitors
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Integrase mutations can reduce the effectiveness of the first-generation FDA-approved integrase strand transfer inhibitors (INSTIs), raltegravir (RAL) and elvitegravir (EVG). The second-generation agent, dolutegravir (DTG), has enjoyed considerable clinical success; however, resistance-causing mutations that diminish the efficacy of DTG have appeared. Our current findings support and extend the substrate envelope concept that broadly effective INSTIs can be designed by filling the envelope defined by the DNA substrates. Previously, we explored 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides as an INSTI scaffold, making a limited set of derivatives, and concluded that broadly effective INSTIs can be developed using this scaffold. Herein, we report an extended investigation of 6-substituents as well the first examples of 7-substituted analogues of this scaffold. While 7-substituents are not well-tolerated, we have identified novel substituents at the 6-position that are highly effective, with the best compound (6p) retaining better efficacy against a broad panel of known INSTI resistant mutants than any analogues we have previously described.
- Zhao, Xue Zhi,Smith, Steven J.,Maskell, Daniel P.,Métifiot, Mathieu,Pye, Valerie E.,Fesen, Katherine,Marchand, Christophe,Pommier, Yves,Cherepanov, Peter,Hughes, Stephen H.,Burke, Terrence R.
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Read Online
- INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS REPLICATION
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Compounds and pharmaceutically acceptable salts thereof, and compositions and methods for treating human immunodeficiency virus (HIV) infection are set forth.
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Page/Page column 63-64
(2020/06/01)
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- Design of Development Candidate eFT226, a First in Class Inhibitor of Eukaryotic Initiation Factor 4A RNA Helicase
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Dysregulation of protein translation is a key driver for the pathogenesis of many cancers. Eukaryotic initiation factor 4A (eIF4A), an ATP-dependent DEAD-box RNA helicase, is a critical component of the eIF4F complex, which regulates cap-dependent protein synthesis. The flavagline class of natural products (i.e., rocaglamide A) has been shown to inhibit protein synthesis by stabilizing a translation-incompetent complex for select messenger RNAs (mRNAs) with eIF4A. Despite showing promising anticancer phenotypes, the development of flavagline derivatives as therapeutic agents has been hampered because of poor drug-like properties as well as synthetic complexity. A focused effort was undertaken utilizing a ligand-based design strategy to identify a chemotype with optimized physicochemical properties. Also, detailed mechanistic studies were undertaken to further elucidate mRNA sequence selectivity, key regulated target genes, and the associated antitumor phenotype. This work led to the design of eFT226 (Zotatifin), a compound with excellent physicochemical properties and significant antitumor activity that supports clinical development.
- Ernst, Justin T.,Thompson, Peggy A.,Nilewski, Christian,Sprengeler, Paul A.,Sperry, Samuel,Packard, Garrick,Michels, Theodore,Xiang, Alan,Tran, Chinh,Wegerski, Christopher J.,Eam, Boreth,Young, Nathan P.,Fish, Sarah,Chen, Joan,Howard, Haleigh,Staunton, Jocelyn,Molter, Jolene,Clarine, Jeff,Nevarez, Andres,Chiang, Gary G.,Appleman, Jim R.,Webster, Kevin R.,Reich, Siegfried H.
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supporting information
p. 5879 - 5955
(2020/07/03)
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- INHIBITORS OF FIBROBLAST ACTIVATION PROTEIN
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Compounds and compositions for modulating fibroblast activation protein (FAP) are described. The compounds and compositions may find use as therapeutic agents for the treatment of diseases, including hyperproliferative diseases.
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Paragraph 0728-0731; 0798-0801
(2019/07/03)
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- Halogenated allyl amine type SSAO/VAP-1 inhibitor and application thereof
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The invention belongs to the technical field of medicine, and particularly relates to a halogenated allyl amine type compound shown as a formula I, medically acceptable salt, ester or stereo isomers thereof, wherein R1, R2, R3, R4, R5, R6, L1, Cy1, R7 and p are defined in description. The invention also relates to a medicine preparation containing the compounds, a medicine composition containing the compounds, and application of the compounds to prevention and/or treatment on diseases relevant to SSAO/VAP 1 protein or diseases caused by SSAO/VAP 1 protein mediating. The formula I is shown in the description.
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Paragraph 0315; 0319-0321
(2019/06/08)
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- ARYLCARBOXAMIDES AND USES THEREOF
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The present disclosure is directed to compounds of formula (I): or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof. Compounds of formula (I) are inhibitors of NOX4 and are useful in the treatment of fibrotic diseases such as scleroderma; lung disease, such as pulmonary fibrosis including idiopathic pulmonary fibrosis (IPF); heart disease, such as heart failure due to ischaemic heart disease, valvular heart disease and hypertensive heart disease, diabetic cardiomyopathy and hypertension; liver disease, such as cirrhosis of the liver; and kidney disease, such as progressive kidney disease glomerulonephritis and diabetic nephropathy; and eye disease such as diabetic retinopathy; skin or subcutaneous scarring, such as keloids, adhesions, hypertrophic scarring or cosmetic scarring; or as an adjuvant or anti-fibrotic in pancreatic cancer to increase chemotherapeutic drug penetration by reducing the density of the connective tissue stroma.
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Paragraph 0278
(2017/12/13)
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- EIF4A-INHIBITING COMPOUNDS AND METHODS RELATED THERETO
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The present invention provides synthesis, pharmaceutically acceptable formulations and uses of compounds in accordance with Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. For Formula I compounds X, Y, R1, R2, R3a, R3b, R4a, R4b and R5 are as defined in the specification. The inventive Formula I compounds are inhibitors of eIF4A and find utility in any number of therapeutic applications, including but not limited to treatment of inflammation and various cancers.
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Paragraph 0684; 0685
(2017/08/01)
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- AROMATIC COMPOUND
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Provided is a novel aromatic ring compound having a GPR40 agonist activity and a GLP-1 secretagogue action. A compound represented by the formula: wherein each symbol is as described in the DESCRIPTION, or a salt thereof has a GPR40 agonist activity and a GLP-1 secretagogue action, is useful for the prophylaxis or treatment of cancer, obesity, diabetes, hypertension, hyperlipidemia, cardiac failure, diabetic complications, metabolic syndrome, sarcopenia and the like, and affords superior efficacy.
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Paragraph 1367; 1368
(2016/05/19)
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- THIOARYL DERIVATIVES AS GPR120 AGONISTS
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The present invention relates to thioaryl derivatives of Formula 1 as defined in the specification, a method for preparing the same, a pharmaceutical composition comprising the same and use thereof. The thioaryl derivatives of Formula 1 according to the present invention promote GLP-1 formation in the gastrointestinal tract and improve insulin resistance in macrophages, pancreas cells, etc. due to anti-inflammatory action, and can accordingly be effectively used for preventing or treating diabetes, complications of diabetes, inflammation, obesity, non-alcoholic fatty liver, steatohepatitis or osteoporosis.
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Paragraph 752-754
(2014/05/24)
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- Total synthesis and stereochemical assignment of baringolin
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The thiopeptide antibiotic baringolin has been synthesized, and its structure and stereochemistry have been confirmed. The use of a strategy based on palladium-catalyzed cross-couplings permitted a modular construction of this natural product. Copyright
- Just-Baringo, Xavier,Bruno, Paolo,Ottesen, Lars K.,Canedo, Librada M.,Albericio, Fernando,Alvarez, Mercedes
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p. 7818 - 7821
(2013/08/23)
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- COMPOUNDS FOR TREATING SPINAL MUSCULAR ATROPHY
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Provided herein are compounds, compositions thereof and uses therewith for treating spinal muscular atrophy.
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Paragraph 00931; 00932
(2013/09/12)
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- First synthesis of methyl 2-amino-6-methoxynicotinate using a combination of microwave and flow reaction technologies
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The synthesis of methyl 2-amino-6-methoxynicotinate, a valuable building block for the preparation of fused 2-pyridones, is reported. The optimized synthesis includes sequential microwave-induced regioselective 6-methoxylation, esterification, followed by microwave-induced reaction with p- methoxybenzylamine, and final deprotection under flow reaction hydrogenation conditions. Two key steps in the reported synthesis are a microwave-induced methoxylation and a microfluidic hydrogenation that afford improved regioselectivity and purity profile of the reaction products. Georg Thieme Verlag Stuttgart.
- Jeges, Gyorgy,Meszaros, Tamas,Szommer, Tamas,Kovacs, Jozsef,Nagy, Tamas,Tymoshenko, Dmytro,Fotouhi, Nader,Gillespie, Paul,Kowalczyk, Agnieszka,Goodnow Jr., Robert A.
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supporting information; experimental part
p. 203 - 206
(2011/03/22)
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- NOVEL COMPOSITIONS AND METHODS OF USE
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Described herein are novel enzyme inhibitors. In some embodiments the enzyme inhibitors are integrase inhibitors, particularly HIV integrase inhibitors. Also described herein are compositions containing them and methods of using them. Thus, the compounds and compositions described herein are useful for the in vitro and in vivo inhibition of HIV integrase as a method of treating or preventing HIV, AIDS or related disorders.
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Page/Page column 70
(2009/09/04)
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- AZAQUINOLONE BASED COMPOUNDS EXHIBITING PROLYL HYDROXYLASE INHIBITORY ACTIVITY, COMPOSITIONS, AND USES THEREOF
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Compounds of Formula (I) are useful as inhibitors of HIF prolyl hydroxylases where the definitions of the variables are provided herein.
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Page/Page column 41
(2008/12/06)
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- NOVEL 1,8-NAPHTHYRIDINE COMPOUNDS
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The present invention relates to naphthyridine compounds useful as HIF prolyl hydroxylase inhibitors to treat anemia and like conditions.
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Page/Page column 25-26
(2008/12/08)
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- Synthesis and structure-affinity relationships of novel N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides with potent serotonin 5-HT3 and dopamine D2 receptor antagonistic activity
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A structurally original series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides derived from the corresponding benzamide 5 were prepared and evaluated for their binding affinity for the dopamine D2 and serotonin 5-HT3 receptors using rat striatum and rat cortical membrane, respectively. Many of the synthesized pyridine-3-carboxamides exhibited nanomolar binding affinity for the serotonin 5-HT3 receptor along with moderate to high binding affinity for the dopamine D2 receptor. Introduction of the more lipophilic bromine atom and methylamino group at the 5- and 6-positions of the pyridine ring, respectively, enhanced the affinity for the dopamine D2 receptor while keeping a potent serotonin 5-HT3 receptor binding affinity. As a result of structure-affinity relationships, the 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxamide 53 was selected as the most promising product showing a high binding affinity for both receptors. Compound 53 affinity for the dopamine D2 and serotonin 5-HT3 receptors was much more potent than that of metoclopramide (dopamine D2 receptor; 23.3 nM vs 444 nM, serotonin 5-HT3 receptor; 0.97 nM vs 228 nM). Optical resolution of the racemate 53 brought about a dramatic change in the pharmacological profile with (R)- 53 exhibiting a strong affinity for both the dopamine D2 and serotonin 5-HT3 receptors, while the corresponding (S)-53 had a potent serotonin 5-HT3 receptor binding affinity and a moderate dopamine D2 receptor binding affinity. X-ray crystallographic study of (R)-53 revealed the existence of two energically stable conformers just like two mirror images. This may account for (R)-53 high affinity for both the dopamine D2 and serotonin 5-HT3 receptors. Pharmacologically, (R)-53 [AS-8112] showed a potent antagonistic activity for both the dopamine D2 and serotonin 5-HT3 receptors in vivo tests and dose-dependently inhibited both the incidence and frequency of emetic episodes induced by cisplatin (ferrets) and morphine (dogs) with ID50 values of 27.1, μg/kg, po and 136 μg/kg, po, respectively. On the basis of this pharmacological profile, (R)-53 is now under further investigation as a potential broad antiemetic agent.
- Hirokawa, Yoshimi,Fujiwara, Iwao,Suzuki, Kenji,Harada, Hiroshi,Yoshikawa, Takashi,Yoshida, Naoyuki,Kato, Shiro
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p. 702 - 715
(2007/10/03)
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- CONTRASTING REACTIONS OF 2,6-DICHLORO-4-TRICHLOROMETHYLPYRIDINE, 2,6-DICHLORO-3-TRICHLOROMETHYLPYRIDINE AND THEIR N-OXIDES WITH NUCLEOPHILES
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Various nucleophiles react with 2,6-dichloro-4-trichloromethylpyridine and 2-chloro-6-trichloromethylpyridine as expected, by displacement of ring chlorine atoms.But in the reactions of nucleophiles with 2,6-dichloro-3-trichloromethylpyridine and 2,6-difluoro-3-trifluoromethylpyridine, displacement of ring halogen atoms is accompained or followed by multiple attack at the trihalogenomethyl group.The reactivity of the trihalogenomethyl groups is modified by N-oxidation.A mechanism for the peculiar reactivity of the trihalogenomethyl groups is proposed, involving loss of halide ion from the CX3 group assisted by Ione pairs on substituents or negative charge in Meisenheimer intermediates.Both geometrical isomers of 1,2-dichloro-1,2-bis(2,6-dichloro-3-pyridyl)ethene are described.
- Dainter, Ronald S.,Suschitzky, Hans,Wakefield, Basil J.
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p. 227 - 234
(2007/10/02)
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