- METHODS OF TREATING CREATINE TRANSPORTER DEFICIENCY
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Disclosed are methods of treating creatine transporter deficiency, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound that increases transport of a substrate by a mutant or wild-type creatine transporter. Also disclosed are methods of increasing transport of guanidinoacetic acid or a salt thereof across the blood-brain barrier of a mammal, and methods of decreasing accumulation or the concentration of guanidinoacetic acid or a salt thereof in a mammalian cell.
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Paragraph 0473-0474
(2021/10/02)
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- SMALL MOLECULES TARGETING MUTANT MAMMALIAN PROTEINS
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Disclosed are compounds, compositions, and methods useful for treating or preventing a disease or disorder associated with a mutation in a protein.
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Paragraph 0612-0613
(2021/12/03)
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- Discovery, synthesis and anti-atherosclerotic activities of a novel selective sphingomyelin synthase 2 inhibitor
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The sphingomyelin synthase 2 (SMS2) is a potential target for pharmacological intervention in atherosclerosis. However, so far, few selective SMS2 inhibitors and their pharmacological activities were reported. In this study, a class of 2-benzyloxybenzamides were discovered as novel SMS2 inhibitors through scaffold hopping and structural optimization. Among them, Ly93 as one of the most potent inhibitors exhibited IC50 values of 91 nM and 133.9 μM against purified SMS2 and SMS1 respectively. The selectivity ratio of Ly93 was more than 1400-fold for purified SMS2 over SMS1. The in vitro studies indicated that Ly93 not only dose-dependently diminished apoB secretion from Huh7 cells, but also significantly reduced the SMS activity and increased cholesterol efflux from macrophages. Meanwhile, Ly93 inhibited the secretion of LPS-mediated pro-inflammatory cytokine and chemokine in macrophages. The pharmacokinetic profiles of Ly93 performed on C57BL/6J mice demonstrated that Ly93 was orally efficacious. As a potent selective SMS2 inhibitor, Ly93 significantly decreased the plasma SM levels of C57BL/6J mice. Furthermore, Ly93 was capable of dose-dependently attenuating the atherosclerotic lesions in the root and the entire aorta as well as macrophage content in lesions, in apolipoprotein E gene knockout mice treated with Ly93. In conclusion, we discovered a novel selective SMS2 inhibitor Ly93 and demonstrated its anti-atherosclerotic activities in vivo. The preliminary molecular mechanism-of-action studies revealed its function in lipid homeostasis and inflammation process, which indicated that the selective inhibition of SMS2 would be a promising treatment for atherosclerosis.
- Li, Yali,Huang, Taomin,Lou, Bin,Ye, Deyong,Qi, Xiangyu,Li, Xiaoxia,Hu, Shuang,Ding, Tingbo,Chen, Yan,Cao, Yang,Mo, Mingguang,Dong, Jibin,Wei, Min,Chu, Yong,Li, Huiti,Jiang, Xian-Cheng,Cheng, Nengneng,Zhou, Lu
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supporting information
p. 864 - 882
(2019/01/04)
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- RORγ MODULATORS
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The invention provides an RORγ receptor agonist comprising a compound of formula (I), wherein the variables are as defined herein. These compounds are analogous to known RORγ receptor antagonists. The invention further provides a method of activating -the nuclear receptor RORγ, comprising -contacting the RORγ with an effective amount or concentration of a compound of the invention; and a method of treating cancer in a patient, comprising administering to the patient an effective dose of a compound of the invention.
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Page/Page column 69
(2018/04/13)
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- A BMS - 191011 synthetic method
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The invention relates to a synthetic method for a compound BMS-191011. The method comprises the following steps: taking 4-trifluoromethyl benzoyl hydrazine as a raw material and performing steps of oxidative carbonylation, methyl protection, halogenation, amination, deprotection and the like to prepare BMS-191011. The synthetic method adopts a CO balloon for replacing phosgene, so that the reaction toxicity is reduced and the reaction operability is improved. The method has the characteristics of simple and easily available raw materials, mild reaction conditions and simple operation process.
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Paragraph 0044; 0045; 0047
(2017/08/23)
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- Discovery of Clinical Candidate 4-[2-(5-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide (PF-05089771): Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7
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A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective NaV1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.
- Swain, Nigel. A.,Batchelor, Dave,Beaudoin, Serge,Bechle, Bruce M.,Bradley, Paul A.,Brown, Alan D.,Brown, Bruce,Butcher, Ken J.,Butt, Richard P.,Chapman, Mark L.,Denton, Stephen,Ellis, David,Galan, Sebastien R. G.,Gaulier, Steven M.,Greener, Ben S.,De Groot, Marcel J.,Glossop, Mel S.,Gurrell, Ian K.,Hannam, Jo,Johnson, Matthew S.,Lin, Zhixin,Markworth, Christopher J.,Marron, Brian E.,Millan, David S.,Nakagawa, Shoko,Pike, Andy,Printzenhoff, David,Rawson, David J.,Ransley, Sarah J.,Reister, Steven M.,Sasaki, Kosuke,Storer, R. Ian,Stupple, Paul A.,West, Christopher W.
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supporting information
p. 7029 - 7042
(2017/09/07)
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- N-Arylsulfonyl Indolines as Retinoic Acid Receptor-Related Orphan Receptor γ (RORγ) Agonists
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The nuclear retinoic acid receptor-related orphan receptor γ (RORγ; NR1F3) is a key regulator of inflammatory gene programs involved in T helper 17 (TH17) cell proliferation. As such, synthetic small-molecule repressors (inverse agonists) targeting RORγ have been extensively studied for their potential as therapeutic agents for various autoimmune diseases. Alternatively, enhancing TH17 cell proliferation through activation (agonism) of RORγ may boost an immune response, thereby offering a potentially new approach in cancer immunotherapy. Herein we describe the development of N-arylsulfonyl indolines as RORγ agonists. Structure–activity studies reveal a critical linker region in these molecules as the major determinant for agonism. Hydrogen/deuterium exchange coupled to mass spectrometry (HDX-MS) analysis of RORγ–ligand complexes help rationalize the observed results.
- Doebelin, Christelle,Patouret, Rémi,Garcia-Ordonez, Ruben D.,Chang, Mi Ra,Dharmarajan, Venkatasubramanian,Kuruvilla, Dana S.,Novick, Scott J.,Lin, Li,Cameron, Michael D.,Griffin, Patrick R.,Kamenecka, Theodore M.
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supporting information
p. 2607 - 2620
(2016/12/09)
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- SELECTIVE NAV1.7 INHIBITORS FOR THE TREATMENT OF DIABETES
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Provided herein are methods for treating or preventing prediabetes or diabetes, or maintaining or lowering blood or plasma glucose or maintaining or lowering blood or plasma glycated hemoglobin comprising administering to a subject in need thereof a therapeutically effective amount of a compound selectively inhibiting NaVl.7. In particular, provided herein are processes for the preparation of and intermediates used in the preparation of compounds selectively inhibiting NaV1.7, such as the compounds of Formula (I) or compounds of Formula (I').
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- SODIUM CHANNEL MODULATORS FOR THE TREATMENT OF PAIN AND DIABETES
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Provided herein are sodium channel modulating Compounds, in particular NaV1.7 modulating compounds of Formula I or compounds of Formula I′: In particular, provided herein are processes for the preparation of, intermediates used in the preparation of, pharmaceutical compositions comprising, and therapeutic methods comprising administering such compounds. In particular, provided herein are compounds for the treatment of pain and diabetes.
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- Cycloalkyl-substituted mesyl benzamide derivatives, and preparation method and medical application thereof
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The invention relates to cycloalkyl-substitutedmesyl benzamide derivatives, and a preparation method and medical application thereof. The invention particularly discloses compounds disclosed as Formula (I) or pharmaceutically acceptable salts, stereoisomers, solvated compounds or prodrugs thereof, and a preparation method and application thereof. All the groups in the formula are defined in the specification.
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Paragraph 0130; 0131; 0134
(2017/08/25)
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- SODIUM CHANNEL MODULATORS FOR THE TREATMENT OF PAIN
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Provided herein are sodium channel modulating Compounds, in particular NaV1.7 modulating compounds of Formula I: In particular, provided herein are processes for the preparation of, intermediates used in the preparation of, pharmaceutical compositions comprising, and therapeutic methods comprising administering such compounds. In particular, provided herein are compounds for the treatment of pain.
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- Structure-activity relationship studies on a novel class of antiproliferative agents derived from Lavendustin A. Part I: Ring A modifications
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The potent antiproliferative agent SDZ LAP 977, which has shown efficacy in a clinical proof of concept study in actinic keratosis patients, has been previously demonstrated to block the cell cycle in mitosis. In the present study, we further explored the mode of action: SDZ LAP 977 binds to the "colchicine binding site" on tubulin and, thus, inhibits tubulin polymerization in vitro. Moreover, we established structure-activity relationships for the effect of modifications in the 2,5-dimethoxyphenyl moiety ("ring A") of the molecule on in vitro antiproliferative activity.
- Nussbaumer, Peter,Winiski, Anthony P.
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p. 7552 - 7560
(2008/12/23)
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- Piperazinyl CCR1 antagonists-optimization of human liver microsome stability
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The synthesis, biological activity, and pharmacokinetic profile of CCR1 antagonists are described.
- Brown, Matthew F.,Bahnck, Kevin B.,Blumberg, Laura C.,Brissette, William H.,Burrell, Sara A.,Driscoll, James P.,Fedeles, Flavia,Fisher, Michael B.,Foti, Robert S.,Gladue, Ronald P.,Guzman-Martinez, Aikomari,Hayward, Matthew M.,Lira, Paul D.,Lillie, Brett M.,Lu, Yi,Lundquist, Greg D.,McElroy, Eric B.,McGlynn, Molly A.,Paradis, Timothy J.,Poss, Christopher S.,Roache, James H.,Shavnya, Andrei,Shepard, Richard M.,Trevena, Kristen A.,Tylaska, Laurie A.
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p. 3109 - 3112
(2008/03/13)
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- Methods of using piperazine derivatives
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The present invention relates to compounds of the formula I and the pharmaceutically acceptable forms thereof; wherein X, Y, a, b, c, d, R1, R2, R3, R4 and R5 are as defined herein. Moreover, the present invention is also directed at pharmaceutical compositions comprising a compound of the formula I and a pharmaceutically acceptable carrier. Furthermore, the present invention is directed at methods of using the herein described compounds and compositions for treating or preventing a disorder or condition that can be treated or prevented by antagonizing the CCR1 receptor in a mammal.
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- PIPERIDINE DERIVATIVES AND THEIR USE AS SELECTIVE INHIBITORS OF MIP-1ALPHA BINDING TO ITS RECEPTOR CCR1
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A compound of the formula (I) wherein a, b, c R1, R2, R3, R4, R5, R6, R7, Q, W, Y, and Z are defined as above , useful as potent and selective inhibitors of MIP-1α (CCL3) binding to its receptor CCR1 found on inflammatory and immunomodulatory cells (preferably leukocytes and lymphocytes).
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- Novel sulfonic acid derivatives
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A compound of the formula or the pharmaceutically acceptable salt thereof; wherein X, Y, a, b, c, d, R1, R2, R3 and R5 are as defined above useful to treat inflammation and other immune disorders.
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