- Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria
-
Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV via binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound 25
- Lapointe, Guillaume,Skepper, Colin K.,Holder, Lauren M.,Armstrong, Duncan,Bellamacina, Cornelia,Blais, Johanne,Bussiere, Dirksen,Bian, Jianwei,Cepura, Cody,Chan, Helen,Dean, Charles R.,De Pascale, Gianfranco,Dhumale, Bhavesh,Fisher, L. Mark,Fulsunder, Mangesh,Kantariya, Bhavin,Kim, Julie,King, Sean,Kossy, Lauren,Kulkarni, Upendra,Lakshman, Jay,Leeds, Jennifer A.,Ling, Xiaolan,Lvov, Anatoli,Ma, Sylvia,Malekar, Swapnil,McKenney, David,Mergo, Wosenu,Metzger, Louis,Mhaske, Keshav,Moser, Heinz E.,Mostafavi, Mina,Namballa, Sunil,Noeske, Jonas,Osborne, Colin,Patel, Ashish,Patel, Darshit,Patel, Tushar,Piechon, Philippe,Polyakov, Valery,Prajapati, Krunal,Prosen, Katherine R.,Reck, Folkert,Richie, Daryl L.,Sanderson, Mark R.,Satasia, Shailesh,Savani, Bhautik,Selvarajah, Jogitha,Sethuraman, Vijay,Shu, Wei,Tashiro, Kyuto,Thompson, Katherine V.,Vaarla, Krishniah,Vala, Lakhan,Veselkov, Dennis A.,Vo, Jason,Vora, Bhavesh,Wagner, Trixie,Wedel, Laura,Williams, Sarah L.,Yendluri, Satya,Yue, Qin,Yifru, Aregahegn,Zhang, Yong,Rivkin, Alexey
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supporting information
p. 6329 - 6357
(2021/06/01)
-
- Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria
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Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven lar
- Skepper, Colin K.,Armstrong, Duncan,Balibar, Carl J.,Bauer, Daniel,Bellamacina, Cornelia,Benton, Bret M.,Bussiere, Dirksen,De Pascale, Gianfranco,De Vicente, Javier,Dean, Charles R.,Dhumale, Bhavesh,Fisher, L. Mark,Fuller, John,Fulsunder, Mangesh,Holder, Lauren M.,Hu, Cheng,Kantariya, Bhavin,Lapointe, Guillaume,Leeds, Jennifer A.,Li, Xiaolin,Lu, Peichao,Lvov, Anatoli,Ma, Sylvia,Madhavan, Shravanthi,Malekar, Swapnil,McKenney, David,Mergo, Wosenu,Metzger, Louis,Moser, Heinz E.,Mutnick, Daniel,Noeske, Jonas,Osborne, Colin,Patel, Ashish,Patel, Darshit,Patel, Tushar,Prajapati, Krunal,Prosen, Katherine R.,Reck, Folkert,Richie, Daryl L.,Rico, Alice,Sanderson, Mark R.,Satasia, Shailesh,Sawyer, William S.,Selvarajah, Jogitha,Shah, Nirav,Shanghavi, Kartik,Shu, Wei,Thompson, Katherine V.,Traebert, Martin,Vala, Anand,Vala, Lakhan,Veselkov, Dennis A.,Vo, Jason,Wang, Michael,Widya, Marcella,Williams, Sarah L.,Xu, Yongjin,Yue, Qin,Zang, Richard,Zhou, Bo,Rivkin, Alexey
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p. 7773 - 7816
(2020/07/21)
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- SYNTHETIC RETINOIDS FOR USE IN RAR ACTIVATION
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The present invention relates to compounds of formula I: in which A1-A7 and R1 to R5 are defined herein, for use in the treatment of a condition or disease which is alleviated by the activation of retinoic acid receptors (RAR). The invention also relates to pharmaceutical compounds comprising such compounds, and related methods of treatment. In an aspect, the invention relates to a method of screening compounds for therapeutic potential in the treatment of a condition or disease which is alleviated by the activation of retinoic acid receptors (RAR). Aspects of the invention relate to novel compounds of formula I in which at least one of A1 to A3 is N or at least one of A4 is CR12 or A5 is CR13 in which R12/R13 is halogen.
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Page/Page column 17-18
(2020/09/27)
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- CANCER TREATMENTS TARGETING CANCER STEM CELLS
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Disclosed are compounds, methods, compositions, and kits that allow for treating cancer by, e.g., targeting cancer stem cells. In some embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, prostate cancer, testicular cancer, or lymphoma. In some embodiments, the cancer is liver cancer, endometrial cancer, leukemia, or multiple myeloma. The compounds utilized in the disclosure are of Formula (0), (O'), and (I):
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Paragraph 0331; 0643-0645
(2019/11/19)
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- NOVEL AROMATIC COMPOUND AND USE THEREOF
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Provided is a compound showing a bone formation promoting action (and/or bone resorption suppressive action). A compound of the formula (I) or a pharmacologically acceptable salt: [wherein each substituent is as defined in the DESCRIPTION], has low toxicity, shows good pharmacokinetics, has an action to promote bone formation, and is useful for the prophylaxis or To treatment of metabolic bone diseases (osteoporosis, fibrous osteitis (hyperparathyroidism), osteomalacia, Paget's disease that influences the systemic bone metabolism parameter etc.) associated with a decrease in the bone formation ability as compared to the bone resorption capacity.
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Paragraph 0799-0801
(2016/08/17)
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- QUINOLONE DERIVATIVES AS ANTIBACTERIALS
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This invention is in the field of medicinal chemistry and relates to compounds, and pharmaceutical compositions thereof, that inhibit bacterial gyrase. The compounds are useful as inhibitors of bacterial gyrase activity and bacterial infections, and have the structure of Formula (I) as further described herein. The invention further provides pharmaceutical compositions comprising a compound of Formula (I) and methods of using the compounds and compositions to treat bacterial infections.
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Page/Page column 101; 102
(2016/04/20)
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- AMINOBENZISOXAZOLE COMPOUNDS AS AGONISTS OF A7-NICOTINIC ACETYLCHOLINE RECEPTORS
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The present invention relates to novel aminobenzisoxazole compounds, and pharmaceutical compositions of the same, that are suitable as agonists or partial agonists of ot7-nAChR, and methods of preparing these compounds and compositions, and the use of these compounds and compositions in methods of maintaining, treating and/or improving cognitive function. In particular, methods of administering the compound or composition to a patient in need thereof, for example a patient with a cognitive deficiency and/or a desire to enhance cognitive function, that may derive a benefit therefrom.
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Paragraph 00357
(2017/01/31)
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- NMDA RECEPTOR MODULATORS AND USES RELATED THERETO
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This disclosure relates to NMDA modulators and used related thereto such as for treatment of central nervous system disorders. In certain embodiments, compounds disclosed herein are NR2C subunit-selective NMDA potentiators. In certain embodiments, the disclosure contemplates compounds and pharmaceutical compositions. In certain embodiments, the disclosure contemplates compounds disclosed herein as prodrugs, optionally substituted with one or more substituents, derivatives, or salts thereof. In certain embodiments, the disclosure relates to methods of treating or preventing nervous system disorders comprising administering an effective amount of a composition comprising compound disclosed herein to a subject in need thereof.
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Page/Page column 28; 42; 43
(2014/03/21)
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- Design, synthesis, and structure-activity relationship of a novel series of GluN2C-selective potentiators
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NMDA receptors are tetrameric complexes composed of GluN1 and GluN2A-D subunits that mediate a slow Ca2+-permeable component of excitatory synaptic transmission. NMDA receptors have been implicated in a wide range of neurological diseases and thus represent an important therapeutic target. We herein describe a novel series of pyrrolidinones that selectively potentiate only NMDA receptors that contain the GluN2C subunit. The most active analogues tested were over 100-fold selective for recombinant GluN2C-containing receptors over GluN2A/B/D-containing NMDA receptors as well as AMPA and kainate receptors. This series represents the first class of allosteric potentiators that are selective for diheteromeric GluN2C-containing NMDA receptors.
- Zimmerman, Sommer S.,Khatri, Alpa,Garnier-Amblard, Ethel C.,Mullasseril, Praseeda,Kurtkaya, Natalie L.,Gyoneva, Stefka,Hansen, Kasper B.,Traynelis, Stephen F.,Liotta, Dennis C.
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supporting information
p. 2334 - 2356
(2014/04/17)
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- ANTIVIRAL COMPOUNDS
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The present invention provides compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.
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Page/Page column 97-98
(2012/09/22)
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- ORTHO AMINOAMIDES FOR THE TREATMENT OF CANCER
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Compounds of formula are HDAC inhibitors. These compounds are useful for the treatment of diseases such as cancer in humans or animals.
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Page/Page column 103
(2010/09/05)
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- PROTEASE INHIBITORS
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Compounds of the formula II: wherein R1 and R2 are independently H, F or CH3; or R1 forms an ethynyl bond and R2 is H or C3-C6 cycloalkyl which is optionally substituted with one
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Page/Page column 29
(2010/04/27)
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- PROTEASE INHIBITORS
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Compounds of the formula II, wherein R3 is C1-C3 alkyl or C3-C6 cycloalkyl, either of which is optionally substituted with one or two methyl and/or a fluoro, trifluoromethyl or methoxy, when R3/
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Page/Page column 24
(2010/04/27)
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- TROPANE COMPOUNDS
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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.
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Page/Page column 369
(2009/05/30)
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- Cysteine Protease Inhibitors
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Compounds of the formula II: wherein R2 is the side chain of leucine, isoleucine, cyclohexylglycine, O-methyl threonine, 4-fluoroleucine or 3-methoxyvaline; R3 is H, methyl or F; Rq is trifluoromethyl and Rq′ is H or Rq and Rq′ define keto; Q is a p-(C1-C6alkylsulphonyl)phenyl- or an optionally substituted 4-(C1-C6alkyl)piperazin-1-yl-thiazol-4-yl- moiety have utility in the treatment of disorders characterized by inappropriate expression or activation of cathepsin K, such as osteoporosis, osteoarthritis, rheumatoid arthritis or bone metastases.
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Page/Page column 21
(2009/02/11)
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- AROMATIC COMPOUND
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An aromatic compound represented by the following formula or a pharmaceutically acceptable salt thereof: , wherein ring A is a heterocyclic ring, ring B is a carbocyclic ring, a heterocyclic ring etc., G1, G2, G3, G4 and G5 are CH or N, X is -NH-, -O-, -CH2-, etc., Y is - CH2-,-CO-,-SO2- etc., Z is a single bond, -CO-, -SO2-, -NH-, -O-, -S-, -CONH-,-SO2NH-, etc., R2 is hydrogen, alkyl, alkoxy, halogen, etc., and R3 is carbocyclic group, heterocyclic group, alkyl, etc., is useful as a controlling agent of the function of CCR4 useful for the treatment or therapy for bronchial asthma, atopic dermatitis, etc.
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Page/Page column 87
(2008/12/07)
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- PROTEASE INHIBITORS
-
Compounds of the formula (II): wherein R2 is the side chain of leucine, isoleucine, cyclohexylglycine, O-methyl threonine, 4-fluoroleucine or 3-methoxyvaline; R3 is H, methyl or fluoro; R4 is C1-C6alkyl; E is a bond or thiazolyl, optionally substituted with methyl or fluoro; n is 0 or 1; or a pharmaceutically acceptable salt, N-oxide or hydrate thereof; have utility in the treatment of disorders characterized by inappropriate expression or activation of cathepsinK, such as osteoporosis, osteoarthritis, rheumatoid arthritis or bone metastases.
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Page/Page column 46
(2008/12/07)
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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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