- Discovery and Preclinical Characterization of Usmarapride (SUVN-D4010): A Potent, Selective 5-HT4Receptor Partial Agonist for the Treatment of Cognitive Deficits Associated with Alzheimer's Disease
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A series of oxadiazole derivatives were synthesized and evaluated as 5-hydroxytryptamine-4 receptor (5-HT4R) partial agonists for the treatment of cognitive deficits associated with Alzheimer's disease. Starting from a reported 5-HT4R antagonist, a systematic structure-activity relationship was conducted, which led to the discovery of potent and selective 5-HT4R partial agonist 1-isopropyl-3-{5-[1-(3-methoxypropyl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate (Usmarapride, 12l). It showed balanced physicochemical-pharmacokinetic properties with robust nonclinical efficacy in cognition models. It also showed disease-modifying potential, as it increased neuroprotective soluble amyloid precursor protein alpha levels, and dose-dependent target engagement and correlation of efficacy with oral exposures. Phase 1 clinical studies have been completed and projected efficacious concentration was achieved without any major safety concerns. Phase 2 enabling long-term safety studies have been completed with no concerns for further development.
- Nirogi, Ramakrishna,Mohammed, Abdul Rasheed,Shinde, Anil Karbhari,Gagginapally, Shankar Reddy,Kancharla, Durga Malleshwari,Ravella, Srinivasa Rao,Bogaraju, Narsimha,Middekadi, Vanaja Reddy,Subramanian, Ramkumar,Palacharla, Raghava Choudary,Benade, Vijay,Muddana, Nageswararao,Abraham, Renny,Medapati, Rajesh Babu,Thentu, Jagadeesh Babu,Mekala, Venkat Reddy,Petlu, Surendra,Lingavarapu, Bujji Babu,Yarra, Sivasekhar,Kagita, Narendra,Goyal, Vinod Kumar,Pandey, Santosh Kumar,Jasti, Venkat
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p. 10641 - 10665
(2021/08/03)
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- Reinvestigation of the structure-activity relationships of isoniazid
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Isoniazid (INH) remains a cornerstone for treatment of drug susceptible tuberculosis (TB), yet the quantitative structure-activity relationships for INH are not well documented in the literature. In this paper, we have evaluated a systematic series of INH analogs against contemporary Mycobacterium tuberculosis strains from different lineages and a few non-tuberculous mycobacteria (NTM). Deletion of the pyridyl nitrogen atom, isomerization of the pyridine nitrogen to other positions, replacement of the pyridine ring with isosteric heterocycles, and modification of the hydrazide moiety of INH abolishes antitubercular activity. Similarly, substitution of the pyridine ring at the 3-position is not tolerated while substitution at the 2-position is permitted with 2-methyl-INH 9 displaying antimycobacterial activity comparable to INH. To assess the specific activity of this series of INH analogs against mycobacteria, we assayed them against a panel of gram-positive and gram-negative bacteria, as well as a few fungi. As expected INH and its analogs display a narrow spectrum of activity and are inactive against all non-mycobacterial strains evaluated, except for 4, which has modest inhibitory activity against Cryptococcus neoformans. Our findings provide an updated analysis of the structure-activity relationship of INH that we hope will serve as useful resource for the community.
- Hegde, Pooja,Boshoff, Helena I.M.,Rusman, Yudi,Aragaw, Wassihun Wedajo,Salomon, Christine E.,Dick, Thomas,Aldrich, Courtney C.
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-
- TBSOTf-promoted versatile N-formylation using DMF at room temperature
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Hydrazides and amines were N-formylated by DMF in the presence of tert-butyldimethylsilyl triflate (TBSOTf) at room temperature, in good to excellent yields.
- Sakurai, Masayoshi,Kawakami, Rina,Kihara, Nobuhiro
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supporting information
p. 1291 - 1294
(2019/04/10)
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- Discovery of a 3,4,5-trisubstituted-1,2,4-triazole agonist with high affinity and selectivity at the somatostatin subtype-4 (sst4) receptor
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A series of compounds containing a 1,2,4-triazole moiety were synthesized, targeting the somatostatin receptor subtype-4 (sst4). Compounds were developed in which the Phe6/Phe7/Phe11, Trp8, and Lys9 mimetic groups were interchanged at positions 3, 4, and 5 of the 1,2,4-triazole ring. The 1,2,4-triazoles containing an 2-(imidazol-4-yl)ethyl substituent at position-3 demonstrated moderate binding affinity at sst4. 1,2,4-Triazoles containing an (indol-3-yl)methyl substituent at position-5 lacked affinity at sst4. The 1,2,4-triazoles containing an aminopropyl group at position-4 showed enhanced binding affinity compared to the 3-position. One compound with an 3-(imidazol-4-yl)propyl group at position-4 (compound 44) imparted high affinity and selectivity at sst4 (sst2A = >10000 nM; sst4 = 19 nM), acting as an agonist (EC50 = 6.8 nM). Docking 44 into a model-built structure of sst4 pointed to differences in its binding versus the other low-affinity compounds and was also in line with one of the two previously reported binding modes. A virtual screening (VS) experiment, employing two separate docking algorithms, was able to score 44 among the top-ranked poses. In summary, compound 44 represents a novel and promising lead structure towards the development of a clinically viable sst4 agonist for the treatment of conditions ranging from Alzheimer's disease to chronic pain.
- Daryaei, Iman,Sandoval, Karin,Witt, Ken,Kontoyianni, Maria,Michael Crider
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supporting information
p. 2083 - 2090
(2019/01/04)
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- ANTIBIOTIC COMPOUNDS
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The present invention relates to antibiotic compounds of formula (I), to compositions containing these compounds and to methods of treating bacterial diseases and infections using the compounds. The compounds find application in the treatment of infection with, and diseases caused by, Gram-positive and/or Gram-negative bacteria, and in particular in the treatment of infection with, and diseases caused by, Neisseria gonorrhoeae.
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Page/Page column 147; 148
(2018/03/25)
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- Triazole alcohol antifungal compound with piperidine oxadiazole side chain and preparation method for compound and application of compound
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The invention relates to the medical technical field and provides 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-(piperidine oxadiazole side chain substituted)-2-propanol compounds in one category. The compound comprises cis-trans-isomers thereof and any mixtures in the forms or pharmaceutical salts thereof. The chemical structural formula of the compound is represented by a formula (I). The invention further provides a preparation method for the compound and an application of the compound in preparing antifungal drugs. From an antifungal experiment, the compound provided by the invention has a very strong antifungal effect on various superficial fungi and deep fungi. Compared with existing clinically applied antifungal drugs such as fluconazole, the compound has the advantages of being efficient, low in toxicity and wide in antifungal spectrum, has relatively good activity on fluconazole drug-resistant bacteria and can be used for preparing antifungal drugs. The formula is shown in the description.
- -
-
Paragraph 0102; 0103
(2016/10/07)
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- SUBSTITUTED INDAZOLE COMPOUNDS, COMPOSITIONS THEREOF, AND METHODS OF TREATMENT THEREWITH
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Provided herein are methods for treating and preventing malaria and/or Babesiosis, the methods comprising administering an effective amount of Indazole Compounds having the formulas: (I)[Formula (I) should be inserted here] or (II)[Formula (II) should be inserted here] wherein R1, R2, R3 and Y are as defined herein.
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-
Paragraph 00174
(2016/06/28)
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- FUSED RING HETEROARYL COMPOUNDS AND THEIR USE AS TRK INHIBITORS
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The disclosure provides novel chemical compounds represented by Formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. The compounds can be used as an inhibitor of Trk and are useful in the treatment of pain, cancer, inflammation, neurodegenerative disease and certain infectious diseases. In some compounds of Formula I, Q is —CH═CR3C(O)NR4R5, —C≡CC(O)NR4R5, or
- -
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Paragraph 0394; 0395
(2016/07/05)
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- Discovery of highly potent triazole antifungal agents with piperidine-oxadiazole side chains
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Due to increasing incidence and mortality of invasive fungal infections, discovery and development of new generations of antifungal agents represents a challenging task. On the basis of our previously reported triazole-benzyloxypiperidinyl lead compound, a series of novel triazole antifungal agents containing piperidine-oxadiazole side chains were rationally designed and synthesized. Most of the target compounds showed excellent inhibitory activity against clinically important fungal pathogens. In particular, compounds 6g (MIC = 0.031 μg mL-1) and 11b (MIC = 0.016 μg mL-1) were highly active against Candida albicans including fluconazole-resistant strains. Moreover, they showed inhibitory activity against hyphal formation with low toxicity, which were promising leads for further development. This journal is
- He, Xiaomeng,Jiang, Yan,Zhang, Yongqiang,Wu, Shanchao,Dong, Guoqiang,Liu, Na,Liu, Yang,Yao, Jianzhong,Miao, Zhenyuan,Wang, Yan,Zhang, Wannian,Sheng, Chunquan
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p. 653 - 664
(2015/04/27)
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- NOVEL COMPOUNDS
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This invention relates to compounds of formula I their use as positive allosteric modulators of mGlu5 receptor activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of neurological and psychiatric disorders associated with glutamate dysfunction such as schizophrenia or cognitive decline such as dementia or cognitive impairment. A, B, X, R1, R2, R3 have meanings given in the description.
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Paragraph 0272; 0273; 0274
(2013/06/27)
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- 1,2,4 -TRIAZOLES AS ALLOSTERIC MODULATORS OF MGLU5 RECEPTOR ACTIVITY FOR THE TREATMENT OF SCHIZOPHRENIA OF DEMENTIA
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This invention relates to compounds of formula (I) their use as positive allosteric modulators of mGlu5 receptor activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of neurological and psychiatric disorders associated with glutamate dysfunction such as schizophrenia or cognitive decline such as dementia or cognitive impairment. A, B, X, R1, R2, R3 have meanings given in the description.
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Page/Page column 75-76
(2013/06/27)
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- NOVEL 2-PIPERIDIN-1-YL-ACETAMIDE COMPOUNDS FOR USE AS TANKYRASE INHIBITORS
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The present invention provides for compounds of formula (I), wherein R1-R5 and L are defined herein. The present invention also provides for pharmaceutical compositions and combinations comprising a compound of formula (I) as well as for the use of such compounds as tankyrase inhibitors and in the treatment of Wnt signaling and tankyrase 1 and 2 signaling related disorders which include, but are not limited to, cancer.
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Page/Page column 63; 95
(2013/03/26)
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- Synthesis of novel 1,2,4-oxadiazoles and analogues as potential anticancer agents
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A library of 3,5-disubstituted-1,2,4-oxadiazoles 7-9 and their bioisosters, 1,3,4-oxadiazole 14 and 1,3,4-thiadiazole 16, were synthesized and evaluated in vitro for their anticancer potential against a panel of six human cancer cell lines. The key step in the synthesis of oxadiazoles 7-9 involve coupling of amidoxime 6 with an appropriate carboxylic acid followed by thermal cyclization. The bioisosteres, 1,3,4-oxadiazole 14 and 1,3,4-thiadiazole 16 were prepared from the reaction of a common precursor diacylhydrazine 13 with thionyl chloride and Lawesson′s reagent, respectively. The anticancer studies on the synthesized compounds revealed that presence of a cyclopentyloxy or n-butyloxy on the C-3 aryl ring and piperdin-4-yl or trichloromethyl at the C-5 position of 1,2,4-oxadiazole is essential for good activity. In particular, 1,2,4-oxadiazole 7i and analogue 1,3,4-thiadiazole 16 exhibited significant activity against DU145 (IC50: 9.3 μM) and MDA-MB-231 (IC 50: 9.2 μM) cell lines, respectively.
- Kumar, Dalip,Patel, Gautam,Chavers, Angela K.,Chang, Kuei-Hua,Shah, Kavita
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scheme or table
p. 3085 - 3092
(2011/07/08)
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- SUBSTITUTED IMIDAZO- AND TRIAZOLOPYRIMIDINES, IMIDAZO- AND PYRAZOLOPYRAZINES AND IMIDAZOTRIAZINES
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The invention relates to substituted imidazo- and triazolopyrimidines, imidazo- and pyrazolopyrazines and imidazotriazines and processes for their preparation, and their use for the manufacture of medicaments for the treatment and/or prophylaxis of diseases, in particular of hematological disorders, preferably of leukopenias and neutropenias.
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Page/Page column 29
(2011/06/26)
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- AZOLE COMPOUND
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[Problems] A compound which is useful as an active ingredient of a pharmaceutical composition for treating neuropathic pain is provided. [Means for Solution] The present inventors have made extensive studies on compounds having an FAAH inhibitory activity
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Page/Page column 15
(2011/04/25)
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- Allosteric inhibitors of Akt1 and Akt2: A naphthyridinone with efficacy in an A2780 tumor xenograft model
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A series of naphthyridine and naphthyridinone allosteric dual inhibitors of Akt1 and 2 have been developed. These compounds have been optimized to have potent dual activity against the activated kinase as well as the activation of Akt in cells. One molecu
- Bilodeau, Mark T.,Balitza, Adrienne E.,Hoffman, Jacob M.,Manley, Peter J.,Barnett, Stanley F.,Defeo-Jones, Deborah,Haskell, Kathleen,Jones, Raymond E.,Leander, Karen,Robinson, Ronald G.,Smith, Anthony M.,Huber, Hans E.,Hartman, George D.
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supporting information; experimental part
p. 3178 - 3182
(2009/04/11)
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- The design and synthesis of potent and cell-active allosteric dual Akt 1 and 2 inhibitors devoid of hERG activity
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This letter details the attenuation of hERG in a class of Akt inhibitors through heteroatom insertions into aromatic rings. The development of a cell-active dual Akt 1 and 2 inhibitors devoid of hERG activity is discussed using structure-activity relationships.
- Siu, Tony,Li, Yiwei,Nagasawa, Johnny,Liang, Jun,Tehrani, Lida,Chua, Peter,Jones, Raymond E.,Defeo-Jones, Deborah,Barnett, Stanley F.,Robinson, Ronald G.
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scheme or table
p. 4191 - 4194
(2009/05/07)
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- AMIDE COMPOUNDS
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The present invention provides compounds represented by the formula (Ie) and the formula (If) wherein each symbol is as defined in the specification. According to the present invention, these compounds have a DGAT inhibitory activity and are useful for the prophylaxis, treatment or improvement of diseases or pathologies caused by high expression or high activation of DGAT
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Page/Page column 151
(2008/06/13)
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- Synthesis of GABAA receptor agonists and evaluation of their α-subunit selectivity and orientation in the GABA binding site
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Drugs used to treat various disorders target GABAA receptors. To develop α subunit selective compounds, we synthesized 5-(4-piperidyl)-3-isoxazolol (4-PIOL) derivatives. The 3-isoxazolol moiety was substituted by 1,3,5-oxadiazol-2-one, 1,3,5-oxadiazol-2-thione, and substituted 1,2,4-triazol-3-ol heterocycles with modifications to the basic piperidine substituent as well as substituents without basic nitrogen. Compounds were screened by [3H]muscimol binding and in patch-clamp experiments with heterologously expressed GABAA αiβ 3γ2 receptors (i = 1-6). The effects of 5-aminomethyl-3H-[1,3,4]oxadiazol-2-one 5d were comparable to GABA for all α subunit isoforms. 5-piperidin-4-yl-3H-[1,3,4]oxadiazol-2-one 5a and 5-piperidin-4-yl-3H-[1,3,4]oxadiazol-2-thione 6a were weak agonists at α2-, α3-, and α5-containing receptors. When coapplied with GABA, they were antagonistic in α2-, α4-, and α6-containing receptors and potentiated α3-containing receptors. 6a protected GABA binding site cysteine-substitution mutants α1F64C and α1S68C from reacting with methanethiosulfonate-ethylsulfonate. 6a specifically covalently modified the α1R66C thiol, in the GABA binding site, through its oxadiazolethione sulfur. These results demonstrate the feasibility of synthesizing α subtype selective GABA mimetic drugs.
- Jansen, Michaela,Rabe, Holger,Strehle, Axelle,Dieler, Sandra,Debus, Fabian,Dannhardt, Gerd,Akabas, Myles H.,Lüddens, Hartmut
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supporting information; experimental part
p. 4430 - 4448
(2009/06/06)
-
- INHIBITORS OF AKT ACTIVITY
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The instant invention provides for substituted naphthyridine compounds that inhibit Akt activity. In particular, the compounds disclosed selectively inhibit one or two of the Akt isoforms. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting Akt activity by administering the compound to a patient in need of treatment of cancer.
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Page/Page column 100
(2010/11/25)
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- INHIBITORS OF AKT ACTIVITY
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The present invention is directed to compounds which contain substituted 5-deazapteridine moieties which inhibit the activity of Akt, a serine/threonine protein kinase. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for treating cancer comprising administration of the compounds of the invention.
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Page/Page column 51-52
(2008/06/13)
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- INHIBITORS OF AKT ACTIVITY
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The present invention is directed to compounds which contain substituted naphthyridines which inhibit the activity of Akt, a serine/threonine protein kinase. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for treating cancer comprising administration of the compounds of the invention. These substituted naphthyridines have unexpected advantageous properties when compared to other naphthyridines reported in PCT publication WO2003/086394, such unexpected advantageous properties may include increased cellular potency/solubility, greater selectivity, enhanced pharmacokinetic properties, lack of off target activity and so on.
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Page/Page column 42; 44-45; 67-68
(2010/11/08)
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- INHIBITORS OF AKT ACTIVITY
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The present invention is directed to compounds which contain substituted pyridazines and pyrimidines moieties which inhibit the activity of Akt, a serine/threonine protein kinase. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for treating cancer comprising administration of the compounds of the invention.
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Page/Page column 46
(2010/02/14)
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