- Discovery of carbon-11 labeled sulfonamide derivative: A PET tracer for imaging brain NLRP3 inflammasome
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We report herein the discovery of a positron emission tomography (PET) tracer for the (NOD)-like receptor protein 3 (NLRP3). Our recent medicinal chemistry campaign on developing sulfonamide-based NLRP3 inhibitors led to an analog, 1, with a methoxy subst
- Xu, Yulong,Xu, Yiming,Blevins, Hallie,Lan, Yu,Liu, Yan,Yuan, Gengyang,Striar, Robin,Zagaroli, Julia S.,Tocci, Darcy R.,Langan, Amelia G.,Zhang, Can,Zhang, Shijun,Wang, Changning
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supporting information
(2021/01/18)
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- COMPOUNDS AS NLRP3 INFLAMMASOME INHIBITORS AND COMPOSITIONS AND USES THEREOF
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Scaffold compounds are used to design small molecule compounds and structure- activity relationship studies identify inhibitors of inflammation· Methods include pharmaceutical compositions of the small molecule compounds to inhibit, prevent and treat dise
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Page/Page column 29
(2021/02/12)
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- Asymmetric total synthesis of (+)-asenapine
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Asymmetric total synthesis of (+)-asenapine, an atypical antipsychotic drug, used for treating schizophrenia and acute mania associated with bipolar disorder, is reported. The key steps are the organocatalytic Michael addition of aldehydes to trans-nitroa
- Szcze?niak, Piotr,Staszewska-Krajewska, Olga,Mlynarski, Jacek
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p. 3225 - 3231
(2019/03/26)
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- Discovery of Second-Generation NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization
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NLRP3 inflammasomes have recently emerged as an attractive drug target for neurodegenerative disorders. In our continuing studies, a new chemical scaffold was designed as selective inhibitors of NLRP3 inflammasomes. Initial characterization of the lead HL
- Jiang, Yuqi,He, Liu,Green, Jakob,Blevins, Hallie,Guo, Chunqing,Patel, Sulay Harsiddhbhai,Halquist, Matthew S.,McRae, MaryPeace,Venitz, Jürgen,Wang, Xiang-Yang,Zhang, Shijun
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p. 9718 - 9731
(2019/11/13)
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- Metal-Free Thermal Activation of Molecular Oxygen Enabled Direct α-CH2-Oxygenation of Free Amines
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Direct oxidation of α-CH2 group of free amines is hard to achieve due to the higher reactivity of amine moiety. Therefore, oxidation of amines involves the use of sophisticated metallic reagents/catalyst in the presence or absence of hazardous oxidants under sensitive reaction conditions. A novel method for direct C-H oxygenation of aliphatic amines through a metal-free activation of molecular oxygen has been developed. Both activated and unactivated free amines were oxygenated efficiently to provide a wide variety of amides (primary, secondary) and lactams under operationally simple conditions without the aid of metallic reagents and toxic oxidants. The method has been applied to the synthesis of highly functionalized amide-containing medicinal drugs, such as O-Me-alibendol and -buclosamide.
- Ghosh, Santanu,Jana, Chandan K.
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p. 260 - 266
(2018/02/19)
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- Iron(III)-Catalyzed Chlorination of Activated Arenes
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A general and regioselective method for the chlorination of activated arenes has been developed. The transformation uses iron(III) triflimide as a powerful Lewis acid for the activation of N-chlorosuccinimide and the subsequent chlorination of a wide range of anisole, aniline, acetanilide, and phenol derivatives. The reaction was utilized for the late-stage mono- and dichlorination of a range of target compounds such as the natural product nitrofungin, the antibacterial agent chloroxylenol, and the herbicide chloroxynil. The facile nature of this transformation was demonstrated with the development of one-pot, tandem, iron-catalyzed dihalogenation processes allowing highly regioselective formation of different carbon-halogen bonds. The synthetic utility of the resulting dihalogenated aryl compounds as building blocks was established with the synthesis of natural products and pharmaceutically relevant targets.
- Mostafa, Mohamed A. B.,Bowley, Rosalind M.,Racys, Daugirdas T.,Henry, Martyn C.,Sutherland, Andrew
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p. 7529 - 7537
(2017/07/26)
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- Synthesis and bioevaluation of substituted chalcones, coumaranones and other flavonoids as anti-HIV agents
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A series of chalcone, flavone, coumaranone and other flavonoid compounds were screened for their anti HIV-1 activity in two cell culture models using TZM-bl and PM1 cells. Within the systems evaluated, the most promising compounds contained either an α- or β-hydroxy-carbonyl motif within their structure (e.g., 8 and 9). Efficacious substituents were identified and used to design new HIV inhibitors with increased potency and lower cytotoxicity. Of the scaffolds evaluated, specific chalcones were found to provide the best balance between anti-HIV potency and low host cell toxicity. Chalcone 8l was shown to inhibit different clinical isolates of HIV in a dose-dependent manner (e.g., IC50 typically ≤ 5 μM). Inhibition of HIV infection experiments using TZM-bl cells demonstrated that chalcone 8l and flavonol 9c had IC50 values of 4.7 μM and 10.4 μM, respectively. These insights were used to design new chalcones 8o and 8p. Rewardingly, chalcones 8o and 8p (at 10 μM) each gave >92% inhibition of viral propagation without impacting PM1 host cell viability. Inhibition of viral propagation significantly increased (60-90%) when PM1 cells were pre-incubated with chalcone 8o, but not with the related flavonol 9c. These results suggested that chalcone 8o may be of value as both a HIV prophylactic and therapy. In summary, O-benzyl-substituted chalcones were identified as promising anti-HIV agents for future investigation.
- Cole, Amy L.,Hossain, Sandra,Cole, Alex M.,Phanstiel, Otto
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p. 2768 - 2776
(2016/06/08)
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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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-
Paragraph 00435; 00436
(2016/06/01)
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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.
- -
-
Paragraph 0735; 0736
(2016/06/06)
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- Highly Regioselective Iodination of Arenes via Iron(III)-Catalyzed Activation of N-Iodosuccinimide
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An iron(III)-catalyzed method for the rapid and highly regioselective iodination of arenes has been developed. Use of the powerful Lewis acid, iron(III) triflimide, generated in situ from iron(III) chloride and a readily available triflimide-based ionic liquid allowed activation of N-iodosuccinimide (NIS) and efficient iodination under mild conditions of a wide range of substrates including biologically active compounds and molecular imaging agents.
- Racys, Daugirdas T.,Warrilow, Catherine E.,Pimlott, Sally L.,Sutherland, Andrew
-
supporting information
p. 4782 - 4785
(2015/10/12)
-
- 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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-
Paragraph 00392-00393
(2014/10/04)
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- Development of flavonoid-based inverse agonists of the key signaling receptor US28 of human cytomegalovirus
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A series of 31 chalcone- and flavonoid-based derivatives were synthesized in good overall yields and screened for their inverse agonist activity on the US28 receptor of human cytomegalovirus (HCMV). With one exception (e.g., 2-(5-bromo-2-methoxyphenyl)-3-hydroxy-4H-chromen-4-one), halogen-substituted flavonoids were typically more potent inverse agonists than their related hydro derivatives. While toxicity could be used to partially explain the inverse agonist activity of some members of the series, 5-(benzyloxy)-2-(5-bromo-2- methoxyphenyl)-4H-chromen-4-one (11b) acted on the US28 receptor as a nontoxic, inverse agonist. The full inverse agonism (efficacy, -89%) and potency (EC 50 = 3.5 μM) observed with flavonoid 11b is especially important as it provides both a new tool to study US28 signaling and a potential platform for the future development of HCMV-targeting drugs.
- Kralj, Ana,Nguyen, Mai-Thao,Tschammer, Nuska,Ocampo, Nicolette,Gesiotto, Quinto,Heinrich, Markus R.,Phanstiel, Otto
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p. 5019 - 5032
(2013/07/26)
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- Catalytic asymmetric conjugate addition of Grignard reagents to coumarins - Synthesis of versatile chiral building blocks
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A new protocol for the Cu-catalysed asymmetric conjugate addition of Grignard reagents to coumarins has been developed. The corresponding products are formed in high yields and enantioselectivities. Through a sequential protocol involving conjugate addition followed by nucleophilic ring opening of the chiral enolate, chiral esters and amides are readily accessible.
- Teichert, Johannes F.,Feringa, Ben L.
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supporting information; experimental part
p. 2679 - 2681
(2011/04/27)
-
- SEVEN-MEMBERED RING COMPOUND, PRODUCTION METHOD THEREOF AND PHARMACEUTICAL USE THEREOF
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A 7-membered heterocyclic compound having the formula (I), or its salt, or a solvate thereof with a chymase inhibitory action and useful for the prevention or treatment of various diseases, in which chymase is involved: a method for producing the same, and a pharmaceutical composition useful for the prevention or treatment of diseases, in which chymase is involved, including the compound of having the formula (I), or its pharmaceutically acceptable salt, or a solvate thereof are provided.
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-
Page/Page column 39-40
(2009/03/07)
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- 7-MEMBERED RING COMPOUND, PROCESS FOR PRODUCING THE SAME, AND MEDICINAL USE THEREOF
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A 7-membered heterocyclic compound having the formula (I), or its salt, or a solvate thereof with a chymase inhibitory action and useful for the prevention or treatment of various diseases, in which chymase is involved: a method for producing the same, and a pharmaceutical composition useful for the prevention or treatment of diseases, in which chymase is involved, including the compound of having the formula (I), or its pharmaceutically acceptable salt, or a solvate thereof are provided.
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Page/Page column 30
(2008/06/13)
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- Synthesis and structure-activity relationships of CP-122,721, a second-generation NK-1 receptor antagonist
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The synthesis and SAR of benzylamine side chain analogs of the NK-1 receptor antagonist CP-99,994 are described. The 5-trifluoromethoxy analog, CP-122,721, shows superior in vivo blockade of NK-1 receptor mediated responses.
- Rosen, Terry J.,Coffman, Karen J.,McLean, Stafford,Crawford, Rosemary T.,Bryce, Dianne K.,Gohda, Yoshiko,Tsuchiya, Megumi,Nagahisa, Atsushi,Nakane, Masami,Lowe III, John A.
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p. 281 - 284
(2007/10/03)
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- 2-Phenyl-4-(aminomethyl)imidazoles as Potential Antipsychotic Agents. Synthesis and Dopamine D2 Receptor Binding
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A series of 2-phenyl-4-(aminomethyl)imidazoles were designed as conformationally restricted analogs of the dopamine D2 selective benzamide antipsychotics.The title compounds were synthesized and tested for blockade of YM-09151 binding in cloned African green monkey dopamine D2 receptor preparations.The binding affinity data thus obtained were compared against that of the benzamides and a previously described series of 2-phenyl-5-(aminomethyl)pyrroles.
- Thurkauf, Andrew,Hutchison, Alan,Peterson, John,Cornfield, Linda,Meade, Robin,et al.
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p. 2251 - 2255
(2007/10/02)
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- RING CHLORINATION OF BENZENOID COMPOUNDS USING CALCIUM HYPOCHLORITE
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Chlorination of activated benzenoid rings is efficiently effected at 0 deg C in aqueous acetone/HOAc using calcium hypochlorite as the chlorinating agent.Good to excellent yields of the chlorinated products are obtained.
- Nwaukwa, Stephen O.,Keehn, Philip M.
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p. 799 - 804
(2007/10/02)
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- Antidepressant (3-aryl-2,3-dihydrobenzofuran-3-yl)alkylamines
-
There are described compounds of the formula STR1 where n is 2 or 3, X and Y are each independently hydrogen, loweralkyl, or halogen, and R1 and R2 are each independently hydrogen, loweralkyl, cyano, beta,beta,beta-trichloroethyoxyca
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-
-
- Benzothiazine derivatives
-
Benzothiazine derivatives of the formula I STR1 with (R(1), R(1)', R(1)", R(4) and R(4)' equal to hydrogen, alkyl, alkoxy, halogen, nitro, hydroxyl, acetamido or amino; R(2) equal to hydrogen, alkyl, alkenyl, phenyl; R(3) equal to hydrogen, alkyl, alkenyl, phenyl; R(5) equal to hydrogen or (C1 -C3)-alkyl; R(6) equal to one of the following groups, STR2 with R(7) and R(8) equal to hydrogen, alkyl, cycloalkyl, phenyl; R(9) equal to hydrogen, alkyl, phenyl, pyridyl, pyrimidinyl or benzoyl; R(10) equal to hydrogen, alkyl, phenyl; R(11) equal to hydrogen, hydroxyl, alkoxy or, together with R(12), a bond; and R(12) equal to hydrogen or, together with R(11), a bond; m equal to 1, 2, 3 or 4; n equal to 0 or 1; p equal to 0, 1, 2, 3 or 4, and X equal to oxygen or two hydrogen atoms, and salts of the compounds of the formula I with physiologically tolerated acids and a process for the preparation of compounds I, likewise a method of treatment of disturbances of the calcium balance of a human body are described.
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-
- THE OXIDATION OF ALDEHYDES TO ACIDS WITH CALCIUM HYPOCHLORITE
-
Calcium hypochlorite is an efficient reagent for the oxidation of aldehydes to the corresponding acids.Reactions are carried out at ambient temperature in aqueous acetonitrile-acetic acid solution.Aliphatic aldehydes and aromatic aldehydes with electron withdrawing groups afford good to excellent yields.Nuclear chlorination is the preferred reaction in aromatic aldehydes with electron donating groups.
- Nwaukwa, Stephen O.,Keehn, Philip M.
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p. 3131 - 3134
(2007/10/02)
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