- Synthesis and biological activity of conformationally restricted indole-based inhibitors of neurotropic alphavirus replication: Generation of a three-dimensional pharmacophore
-
We have previously reported the development of indole-based CNS-active antivirals for the treatment of neurotropic alphavirus infection, but further optimization is impeded by a lack of knowledge of the molecular target and binding site. Herein we describe the design, synthesis and evaluation of a series of conformationally restricted analogues with the dual objectives of improving potency/selectivity and identifying the most bioactive conformation. Although this campaign was only modestly successful at improving potency, the sharply defined SAR of the rigid analogs enabled the definition of a three-dimensional pharmacophore, which we believe will be of value in further analog design and virtual screening for alternative antiviral leads.
- Barraza, Scott J.,Sindac, Janice A.,Dobry, Craig J.,Delekta, Philip C.,Lee, Pil H.,Miller, David J.,Larsen, Scott D.
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supporting information
(2021/06/18)
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- KINASE ANTAGONISTS AND METHODS FOR MAKING AND USING THEM
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Disclosed herein are small molecule compounds that are SGK1 antagonists, formulations and pharmaceutical compositions comprising the compounds, and methods of making and using them, for treating, ameliorating, preventing, reversing or slowing the progression of: a cancer, a tumor, a metastasis or a dysplastic or a dysfunctional cell condition responsive to inhibition of a kinase enzyme of the AGC group of kinases including SGK1, by administration of an AGC kinase inhibitor or antagonist.
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Page/Page column 132-133
(2020/02/19)
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- CASPASE INHIBITOR AND PHARMACEUTICAL COMPOSITION, USE AND THERAPEUTIC METHOD THEREOF
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Disclosed are a class of compounds as a caspase inhibitor, and in particular the compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, and the use of the compound in treating caspase-related diseases.
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Paragraph 0185; 0186
(2019/04/05)
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- Novel heterocyclic derivative capable of being used as SHP2 inhibitor
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The invention relates to a novel heterocyclic derivative capable of being used as an SHP2 inhibitor, specifically relates to a compound shown by a formula I or pharmaceutically acceptable salts thereof, further relates to a use of the compound shown by the formula I or the pharmaceutically acceptable salts thereof and a pharmaceutical composition thereof in drug preparation, and particularly relates to a use in preparation of drugs for treatment, inhibition or prevention of diseases or discomforts mediated by SHP2 activity.
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Paragraph 0283
(2019/08/30)
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- NOVEL HETEROCYCLIC DERIVATIVES USEFUL AS SHP2 INHIBITORS
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This invention relates to certain novel pyrazine derivatives (Formula I) as SHP2 inhibitors which is shown as formula I, their synthesis and their use for treating a SHP2 mediated disorder. More particularly, this invention is directed to fused heterocyclic group derivatives useful as inhibitors of SHP2, methods for producing such compounds and methods for treating a SHP2-mediated disorder.
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Paragraph 61
(2018/10/19)
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- Pyrazolopyrimidines as Potent Stimulators for Transient Receptor Potential Canonical 3/6/7 Channels
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Transient receptor potential canonical 3/6/7 (TRPC3/6/7) are highly homologous receptor-operated nonselective cation channels. Despite their physiological significance, very few selective and potent agonists are available for functional examination of these channels. Using a cell-based high throughput screening approach, a lead compound with the pyrazolopyrimidine skeleton was identified as a TRPC6 agonist. Synthetic schemes for the lead and its analogues were established, and structural-activity relationship studies were carried out. A series of potent and direct agonists of TRPC3/6/7 channels were identified, and among them, 4m-4p have a potency order of TRPC3 > C7 > C6, with 4n being the most potent with an EC50 of 20 nM on TRPC3. Importantly, these compounds exhibited no stimulatory activity on related TRP channels. The potent and selective compounds described here should be suitable for evaluation of the roles of TRPC channels in the physiology and pathogenesis of diseases, including glomerulosclerosis and cancer.
- Qu, Chunrong,Ding, Mingmin,Zhu, Yingmin,Lu, Yungang,Du, Juan,Miller, Melissa,Tian, Jinbin,Zhu, Jinmei,Xu, Jian,Wen, Meng,Er-Bu,Wang, Jule,Xiao, Yuling,Wu, Meng,McManus, Owen B.,Li, Min,Wu, Jilin,Luo, Huai-Rong,Cao, Zhengyu,Shen, Bing,Wang, Hongbo,Zhu, Michael X.,Hong, Xuechuan
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p. 4680 - 4692
(2017/06/13)
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- FUSED TRICYCLIC IMIDAZOLE DERIVATIVES AS MODULATORS OF TNF ACTIVITY
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A series of substituted fused tricyclic imidazole derivatives, in particular dihydro- 1H-pyrano[4',3':4,5]imidazo[1,2-a]pyridine, 1,2,3,4-tetrahydroimidazo[1,2-a:5,4- c']dipyridine, dihydro-1H-pyrano[3',4':4,5]imidazo[1,2-a]pyridine and tetrahydro-6H- cyc
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Page/Page column 113; 114
(2015/06/25)
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- FUSED TRICYCLIC BENZIMIDAZOLES DERIVATIVES AS MODULATORS OF TNF ACTIVITY
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A series of tricyclic benzimidazole derivatives, in particular dihydro-1H- imidazo [1,2-a]benzimidazo le, dihydro-1H-pyrrolo [1,2-a]benzimidazo le, dihydro-1H- pyrazino[1,2-a]benzimidazole, dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole and dihydrothiazolo[3,4-a]benzimidazolem, and analogues thereof, being potent modulators of human TNFa activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.
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Page/Page column 117
(2015/06/25)
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- TNF -Alpha Modulating Benzimidazoles
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A series of benzimidazole derivatives, being potent modulators of human TNFα activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.
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Paragraph 0581
(2015/06/10)
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- Synthesis and SAR of Imidazo[1,5-a[pyridine derivatives as 5-HT4 receptor partial agonists for the treatment of cognitive disorders associated with Alzheimer's disease
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Alzheimer's disease (AD) is a neurodegenerative disease which has a higher prevalence and incidence in older people. The need for improved AD therapies is unmet. The 5-hydroxytryptamine4 receptor (5-HT4R) partial agonists may be of benefit for both the symptomatic and disease-modifying treatment of cognitive disorders associated with AD. Herein, we report the design, synthesis and SAR of imidazo[1,5-a] pyridine derivatives as 5-HT4R partial agonists. The focused SAR, optimization of ADME properties resulted the discovery of compound 5a as potent, selective, brain penetrant 5-HT4 partial agonist as a lead compound with good ADME properties and efficacy in both symptomatic and disease modifying animal models of cognition.
- Nirogi, Ramakrishna,Mohammed, Abdul Rasheed,Shinde, Anil K.,Bogaraju, Narsimha,Gagginapalli, Shankar Reddy,Ravella, Srinivasa Rao,Kota, Laxman,Bhyrapuneni, Gopinadh,Muddana, Nageswara Rao,Benade, Vijay,Palacharla, Raghava Chowdary,Jayarajan, Pradeep,Subramanian, Ramkumar,Goyal, Vinod Kumar
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supporting information
p. 289 - 301
(2015/09/21)
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- Discovery of novel N-substituted oxindoles as selective M1 and M4 muscarinic acetylcholine receptors partial agonists
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Activation of the M1 and M4 muscarinic acetylcholine receptors is thought to play an important role in improving the symptoms of schizophrenia. However, discovery of selective agonists for these receptors has been a challenge, consid
- Sumiyoshi, Takaaki,Enomoto, Takeshi,Takai, Kentaro,Takahashi, Yoko,Konishi, Yasuko,Uruno, Yoshiharu,Tojo, Kengo,Suwa, Atsushi,Matsuda, Harumi,Nakako, Tomokazu,Sakai, Mutsuko,Kitamura, Atsushi,Uematsu, Yasuaki,Kiyoshi, Akihiko
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supporting information
p. 244 - 248
(2013/03/29)
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- Antibacterial Compounds
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The present invention provides a compound of the following formula, salts, racemates, diastereomers, enantiomers, esters, carbamates, phosphates, sulfates, deuterated forms and prodrugs thereof. Also provided is the use of these compounds as antibacterials, compositions comprising them and processes for their manufacture.
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Paragraph 0465
(2013/10/07)
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- Design, synthesis and biological evaluation of α-substituted isonipecotic acid benzothiazole analogues as potent bacterial type II topoisomerase inhibitors
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The discovery and optimisation of a new class of benzothiazole small molecules that inhibit bacterial DNA gyrase and topoisomerase IV are described. Antibacterial properties have been demonstrated by activity against DNA gyrase ATPase and potent activity against Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes and Haemophilus influenzae. Further refinements to the scaffold designed to enhance drug-likeness included analogues bearing an α-substituent to the carboxylic acid group, resulting in excellent solubility and favourable pharmacokinetic properties.
- Axford, Lorraine C.,Agarwal, Piyush K.,Anderson, Kelly H.,Andrau, Laura N.,Atherall, John,Barker, Stephanie,Bennett, James M.,Blair, Michael,Collins, Ian,Czaplewski, Lloyd G.,Davies, David T.,Gannon, Carlie T.,Kumar, Dushyant,Lancett, Paul,Logan, Alastair,Lunniss, Christopher J.,Mitchell, Dale R.,Offermann, Daniel A.,Palmer, James T.,Palmer, Nicholas,Pitt, Gary R.W.,Pommier, Stéphanie,Price, Daniel,Narasinga Rao,Saxena, Rashmi,Shukla, Tarun,Singh, Amit K.,Singh, Mahipal,Srivastava, Anil,Steele, Christopher,Stokes, Neil R.,Thomaides-Brears, Helena B.,Tyndall, Edward M.,Watson, David,Haydon, David J.
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p. 6598 - 6603
(2014/01/06)
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- ANTIBACTERIAL COMPOUNDS
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The present invention provides a compound of the following formula and salts thereof: Also provided is the use of these compounds as antibacterials, compositions comprising them and processes for their manufacture.
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Page/Page column 17; 18
(2012/04/18)
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- Novel piperidinyl monocarboxylic acids as S1P1 receptor agonists
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The present invention relates to novel compounds acting as agonists at S1P (sphingosine-1-phosphate) receptors, compositions containing these compounds, use of these compounds in medicine and their process of preparation.
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Page/Page column 15
(2012/11/06)
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- NOVEL PIPERIDINYL MONOCARBOXYLIC ACIDS AS S1P1 RECEPTOR AGONISTS
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The present invention relates to novel compounds acting as agonists at S1P (sphingosine-1-phosphate) receptors, compositions containing these compounds, use of these compounds in medicine and their process of preparation.
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Page/Page column 31-32
(2012/11/06)
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- AMINOPYRIMIDINES USEFUL AS KINASE INHIBITORS
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The present invention relates to compounds useful as inhibitors of Aurora protein kinases. The invention also provides pharmaceutically acceptable compositions comprising those compounds and methods of using the compounds and compositions in the treatment
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Page/Page column 36
(2010/06/16)
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- Development of a scalable synthesis of dipeptidyl peptidase-4 inhibitor ABT-279
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A convergent, scalable synthesis of dipeptidyl peptidase-4 inhibitor, ABT-279, has been developed and demonstrated on multikilogram scale. The cis-2,5-disubstituted pyrrolidine is generated by cyclization of a Boc-amine onto an alkynyl ketone followed by stereospecific reduction of the resulting acyliminium intermediate. The amine coupling partner was prepared by a novel Hofmann rearrangement promoted by 1,3-dibromo-5,5-dimethylhydantoin. The final product was isolated as the L-malic acid salt. The scaleup campaign consisted of 15 steps and delivered 42 kg of ABT-279 in 14% overall yield. A second-generation synthesis that addresses some of the issues encountered during scale-up was developed and demonstrated on kilogram scale.
- McDermott, Todd S.,Bhagavatula, Lakshmi,Borchardt, Thomas B.,Engstrom, Kenneth M.,Gandarilla, Jorge,Kotecki, Brian J.,Kruger, Albert W.,Rozema, Michael J.,Sheikh, Ahmad Y.,Wagaw, Seble H.,Wittenberger, Steven J.
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experimental part
p. 1145 - 1155
(2010/04/22)
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- IMIDAZO[1,2-A]PYRIDINE COMPOUNDS AS RECEPTOR TYROSINE KINASE INHIBITORS
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Compounds of Formula (I) in which A, B, R1, R1a, R2, R3, R4, R5, R6, R7 and R8 have the meanings given in the specification, are receptor tyrosine inhibitors useful in the treatment of diseases mediated by class 3 and class 5 receptor tyrosine kinases. Particular compounds of this invention have also been found to be inhibitors of Pim-1
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- SYNTHESIS OF (2S,5R)-5-ETHYNYL-1-{N-(4-METHYL-1-(4-CARBOXY-PYRIDIN-2-YL)PIPERIDIN-4-YL)GLYCYL}PYRROLIDINE-2-CARBONITRILE
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A process for making (2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile and salts thereof, and intermediates used in the process are disclosed.
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Page/Page column 38
(2008/06/13)
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- HETEROCYCLIC-SUBSTITUTED PIPERDINE COMPOUNDS AND THE USES THEREOF
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The invention relates to Heterocyclic-Substituted Piperidine Compounds, compositions comprising an effective amount of a Heterocyclic-Substituted Piperidine Compound and methods to treat or prevent a condition, such as pain, comprising administering to an animal in need thereof an effective amount of a Heterocyclic-Substituted Piperidine Compound
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Page/Page column 233
(2008/12/07)
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- NOVEL BENZAMIDINE COMPOUND
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The present invention relates to a novel compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof. wherein each symbol is as defined in the specification. According to the present invention, an activated blood coagul
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- NOVEL BENZAMIDINE COMPOUND
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A novel compound, or a pharmaceutically acceptable salt thereof, represented by the formula (1) wherein the characters are as defined in the description. Thus, there can be provided an activated blood coagulation factor X inhibitor and a novel anti(blood)
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Page/Page column 36-37
(2008/06/13)
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- PYRIDINE DERIVATIVES AND USE THEREOF AS UROTENSIN II ANTAGONISTS
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The invention relates to novel pyridine derivatives of formula 1 and related compounds and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and their use as neurohormonal antagonists, especially as urotensin II inhibitors.
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Page/Page column 46
(2008/06/13)
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- Facile synthesis of 4-substituted-4-aminopiperidine derivatives, the key building block of piperazine-based CCR5 antagonists
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4-Substituted-4-aminopiperidine is an interesting structural motif found in a number of bioactive compounds. An efficient and convenient method for the synthesis of 4-differently substituted-4-aminopiperidine derivatives was described, employing isonipecotate as a starting material and Curtius rearrangement as a key step. The alkylation of isonipecotate could introduce various substituents at the 4-position of the piperidine ring. With this key building block, we are able to efficiently synthesize piperazino-piperidine based CCR5 antagonist in a highly convergent manner free of using toxic reagents such as diethylaluminum cyanide. The concise synthesis of a potent bioavailable CCR5 antagonist as HIV-1 entry inhibitor, Sch-350634 (1) was accomplished in excellent yield using N′-Boc-4-methyl-4-aminopiperidine 5a as a smart building block. The new methodology provides a facile and practical access to the piperazino-piperidine amide analogs as HIV-1 entry inhibitors.
- Jiang, Xiao-Hua,Song, Yan-Li,Long, Ya-Qiu
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p. 3675 - 3678
(2007/10/03)
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- N-acylsulfonamide apoptosis promoters
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N-Benzoyl arylsulfonamides having the formula are BCL-Xl inhibitors and are useful for promoting apoptosis. Also disclosed are BCL-Xl inhibiting compositions and methods of promoting apoptosis in a mammal.
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- N-Acylsulfonamide apoptosis promoters
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N-Benzoyl arylsulfonamides having the formula Are BCL-X1 inhibitors and are useful for promoting apoptosis. Also disclosed are BCL-X1 inhibiting compositions and methods of promoting apoptosis in a mammal.
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- N-acyl cyclic amine derivatives
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The invention relates to compounds represented by the general formula [I][wherein Ar means an aryl group or a heteroaryl group which may have a substitutive group selected from a group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group; R1 means a C3-C6 cycloalkyl group which is substitutable with a fluorine atom; R2 and R4 mean hydrogen atoms, groups represented by -(A1)m-NH-B or the like; R3 and R5 mean hydrogen atoms, C1-C6 aliphatic hydrocarbon groups or the like which are substitutable with a lower alkyl group(s); n means 0 or 1; and X means an oxygen atom or a sulfur atom]. Compounds according to the invention, since they not only have potent selective antagonistic activity against muscarinic M3 receptors but also exhibit excellent oral activity, durability of action and pharmacokinetics, are very useful as safe and effective remedies against respiratory, urinary and digestive diseases with little adverse side effects.
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