- INSULIN CONJUGATES
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The present invention relates to a conjugate comprising a sulfonamide of formula (I) and an active pharmaceutical ingredient such as an insulin analog comprising at least one mutation relative to the parent insulin, wherein the insulin analog comprises a mutation at position B16 which is substituted with a hydrophobic amino acid and/or a mutation at position B25 which is substituted with a hydrophobic amino acid. The present invention further relates to a sulfonamide of formula (A). Moreover, the present invention relates to an insulin analog comprising at least one mutation relative to the parent insulin.
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Paragraph 0628; 0635-0638
(2020/07/05)
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- COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY
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In one aspect, compounds of Formula A, or a pharmaceutically acceptable salt thereof, are featured (Formula A) or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula A can be as defined anywhere herein.
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Page/Page column 335-336
(2020/06/10)
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- NLRP3 INHIBITORS
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The present application relates to compounds with NLRP3inhibitory activity and to associated salts, solvates, prodrugs and pharmaceutical compositions. The present application further relates to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by NLRP3inhibition.
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Page/Page column 83-84
(2020/06/10)
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- SULPHONAMIDES AND COMPOSITIONS THEREOF FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY
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In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured: wherein the variables shown in Formula AA can be as defined anywhere herein. Compounds AA are modulators of NLRP1 and/or NLRP3
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Page/Page column 481
(2019/05/10)
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- Design, Synthesis, and X-ray of Selenides as New Class of Agents for Prevention of Diabetic Cerebrovascular Pathology
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A series of novel selenides bearing benzenesulfonamide moieties was synthesized and investigated for their inhibition on six human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms such as the physiologically relevant hCA I, II, VA, VB, VII, and IX and the
- Angeli, Andrea,Di Cesare Mannelli, Lorenzo,Trallori, Elena,Peat, Thomas S.,Ghelardini, Carla,Carta, Fabrizio,Supuran, Claudiu T.
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p. 462 - 467
(2018/05/23)
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- Targeted Polypharmacology: Discovery of a Highly Potent Non-Hydroxamate Dual Matrix Metalloproteinase (MMP)-10/-13 Inhibitor
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Matrix metalloproteinases (MMPs) play a key role in many diseases like cancer, atherosclerosis or arthritis. Interest in MMP inhibition has been revitalized very recently as the knowledge on the underlying network of biological pathways is steadily growing. On the basis of this new insight into the relevance of MMP-10 and MMP-13 within the MMP network and the ban of hydroxamate inhibitors from clinical development, the discovery of non-hydroxamate multitarget drugs against specific MMPs is of foremost interest. Here, we disclose the discovery of a very potent and selective non-hydroxamate MMP-10/-13 inhibitor. The high potency (IC50 of 31 nM [MMP-10] and 5 nM [MMP-13]) and selectivity over MMP-1, -2, -3, -7, -8, -9, -12, and -14 enable this compound to decipher disease causing MMP networks and to generate new treatment options through targeted polypharmacology.
- Senn, Nicole,Ott, Michael,Lanz, Jan,Riedl, Rainer
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p. 9585 - 9598
(2017/12/26)
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- SUBSTITUTED PYRIDINES AS INHIBITORS OF DNMT1
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The invention is directed to substituted pyridine derivatives. Specifically, the invention is directed to compounds according to Formula (Iar): (Iar) wherein Yar, X1ar, X2ar, R1ar, R2ar, R3ar, R4ar and R5ar are as defined herein; or a pharmaceutically acceptable salt or prodrug thereof. The compounds of the invention are selective inhibitors of DNMT1 and can be useful in the treatment of cancer, pre-cancerous syndromes, beta hemoglobinopathy disorders, sickle cell disease, sickle cell anemia, and beta thalassemia, and diseases associated with DNMT1 inhibition. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting DNMT1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
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Page/Page column 629
(2018/01/20)
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- ACYLSULFONAMIDES AND PROCESSES FOR PRODUCING THE SAME
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The present disclosure relates to acylsulfonamides and processes for their preparation. The processes involve a target-guided synthesis approach, whereby a thioacid and a sulfonyl azide are reacted in the presence of a biological target protein, a Bcl-2 family protein, to form the acylsulfonamide.
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Page/Page column 113; 114
(2012/03/09)
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- Design, synthesis, and invitro antifungal activity of 1-[(4-substituted-benzyl)methylamino]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ols
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As part of our studies focused on the design of 1-[((hetero)aryl- and piperidinylmethyl)amino]-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propan-2-ols as antifungal agents, we report the development of new extended benzylamine derivatives substituted at the para p
- Guillon, Remi,Pagniez, Fabrice,Giraud, Francis,Crepin, Damien,Picot, Carine,LeBorgne, Marc,Morio, Florent,Duflos, Muriel,Loge, Cedric,LePape, Patrice
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experimental part
p. 816 - 825
(2012/01/06)
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- DESIGN, SYNTHESIS AND EVALUATION OF PROCASPASE ACTIVATING COMPOUNDS AS PERSONALIZED ANTI-CANCER DRUGS
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Compositions and methods are disclosed in embodiments relating to induction of cell death such as in cancer cells. Compounds and related methods for synthesis and use thereof, including the use of compounds in therapy for the treatment of cancer and selective induction of apoptosis in cells are disclosed. Compounds are disclosed that have lower neurotoxicity effects than other compounds.
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Page/Page column 69
(2010/08/18)
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- PHOSPHODIESTERASE-4 INHIBITORS BELONGING TO THE TERTIARY AMINE CLASS
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Compounds of formula (I): wherein n, A, R1, and R2 are defined in the specification, are useful as inhibitors of the phosphodiesterase 4 (PDE4) enzyme and for treating certain conditions.
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Page/Page column 8
(2009/10/21)
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- NOVEL 1,2,3-TRIAZOLE DERIVATIVES USEFUL AS MODULATORS OF NICOTINIC ACETYLCHOLINE RECEPTORS
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This invention relates to novel 1,2,3-triazole derivatives, which are found to be modulators of the nicotinic acetylcholine receptors. Due to their pharmacological profile,the compounds of the invention may be useful for the treatment of diseases or disor
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Page/Page column 12-13
(2009/10/22)
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- Bcl-XL-templated assembly of its own protein-protein interaction modulator from fragments decorated with thio acids and sulfonyl azides
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Protein-protein interactions have key importance in various biological processes and modulation of particular protein-protein interactions has been shown to have therapeutic effects. However, disrupting or modulating protein-protein interactions with low-molecular-weight compounds is extremely difficult due to the lack of deep binding pockets on protein surfaces. Herein we describe the development of an unprecedented lead synthesis and discovery method that generates only biologically active compounds from a library of reactive fragments. Using the protein Bcl-XL, a central regulator of programmed cell death, we demonstrated that an amidation reaction between thio acids and sulfonyl azides is applicable for Bcl-XL-templated assembly of inhibitory compounds. We have demonstrated for the first time that kinetic target-guided synthesis can be applied not only on enzymatic targets but also for the discovery of small molecules modulating protein-protein interactions. Copyright
- Hu, Xiangdong,Sun, Jiazhi,Wang, Hong-Gang,Manetsch, Roman
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supporting information; experimental part
p. 13820 - 13821
(2009/02/07)
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- Further optimization of sulfonamide analogs as EP1 receptor antagonists: Synthesis and evaluation of bioisosteres for the carboxylic acid group
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4-{[2-[(2-Furylsulfonyl)(isobutyl)amino]-5-(trifluoromethyl)phenoxy]methyl}benzoic acid analogs 2a and b and a series of the acid analogs, in which the carboxylic acid residue of 2b was replaced with various kinds of carboxylic acid bioisosteres, were synthesized and evaluated as EP1 receptor antagonists. Compound 2b and its monocyclic acid analogs, in which the carboxylic acid residue of 2b was replaced with monocyclic acid bioisosteres, were found to show potent EP1 receptor antagonist activity. Optimization of the linker Y between the phenyl moiety and the carboxylic acid residue of 2b was also carried out (Table 5). Compounds 2b and 16 and 17 possessing conformationally restricted linker Y were found to show the most optimized potency among the tested compounds. Cytochrome P450 inhibition of optimized compounds was also investigated. Details of the structure-activity relationship study are presented.
- Naganawa, Atsushi,Matsui, Toshiaki,Ima, Masaki,Saito, Tetsuji,Murota, Masayuki,Aratani, Yoshiyuki,Kijima, Hideomi,Yamamoto, Hiroshi,Maruyama, Takayuki,Ohuchida, Shuichi,Nakai, Hisao,Toda, Masaaki
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p. 7121 - 7137
(2007/10/03)
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- NOVEL SULFONAMIDE DERIVATIVE
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A compound of the formula (1): wherein m, n and p is independently an integer of 0 to 4 with the proviso that 3 a?| m + n a?| 8; X is the formula: NR4, etc.; R1, R3 and R4 are a substituted or unsubstituted aryl group, etc.; R2 is a hydrogen atom, etc.; a, b, c, d, e and f are a hydrogen atom or a substituted or unsubstituted alkyl group, etc.; Y is the formula: -SO2-, etc.; and Z is an oxygen atom, etc.; or a prodrug thereof or a pharmaceutically acceptable salt of the same has an activity of potentiating an expression of a low density lipoprotein receptor and thus is useful as an agent for treating hyperlipidemia or arteriosclerosis.
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Page/Page column 63
(2010/11/25)
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- A structure-Permeability study of small drug-like molecules
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A systematic structure-permeability relationship study on a set of small drug-like molecules with log D values in the range -2.5 to 3 and carrying a diverse array of functionality reveals that the compounds with log D>0 and 3 are highly permeable. Surprisingly, several tetrazole derivatives were found to be substrates for efflux pump(s).
- Fichert, Thomas,Yazdanian, Mehran,Proudfoot, John R.
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p. 719 - 722
(2007/10/03)
-
- Antitumor agents. Part 3: Synthesis and cytotoxicity of new trans-stilbene benzenesulfonamide derivatives
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A new series of trans-stilbene benzenesulfonamide derivatives were designed and synthesized as potential antitumor agents. These new compounds were evaluated in the National Cancer Institute's 60 human tumor cell line in vitro screen. Compounds 9-13 were cytotoxic against several cell lines. Notably, two compounds, 9 and 12, demonstrated selective cytotoxic activity against BT-549 breast cancer (GI50=0.205 μM) and HT-29 colon cancer (GI50=0.554 μM), respectively.
- Yang, Li-Ming,Lin, Shwu-Jiuan,Hsu, Fen-Lin,Yang, Tsang-Hsiung
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p. 1013 - 1015
(2007/10/03)
-
- A novel series of selective leukotriene antagonists: Exploration and optimization of the acidic region in 1,6-disubstituted indoles and indazoles
-
A systematic structure-activity exploration of the carboxylic acid region in a series of indole- or indazole-derived leukotriene antagonists 1 led to several discoveries. Use of the 3-methoxy-p-tolyl fragment (illustrated in acid 1) for connecting the indole and the acidic site provides the most potent carboxylic acids 1, tetrazoles 20, and aryl sulfonimides 21. The aryl sulfonimides are 5-500 times more potent (in vitro and/or in vivo) than the corresponding carboxylic acids 1. The o-tolyl sulfonimides such as 114 show greater oral potency than the phenyl sulfonimides at a given level of in vitro activity. Acidic keto sulfone derivatives 10 (Nu = CH(CO2CH3)SO2Ph) mimic the activity of the sulfonimides.
- Yee,Bernstein,Adams,Brown,Cronk,Hebbel,Vacek,Krell,Snyder
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p. 2437 - 2451
(2007/10/02)
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