- Novel benzenesulfonamide-bearing pyrazoles and 1,2,4-thiadiazoles as selective carbonic anhydrase inhibitors
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Two series comprising 20 novel benzenesulfonamides bearing thioureido-linked pyrazole 8 and amino-1,2,4-thiadiazole 10 were synthesized and assayed as human carbonic anhydrase (hCA) inhibitors against isoforms I and II as well as the tumor-associated isof
- Kumar, Rajiv,Kumar, Amit,Ram, Sita,Angeli, Andrea,Bonardi, Alessandro,Nocentini, Alessio,Gratteri, Paola,Supuran, Claudiu T.,Sharma, Pawan K.
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- Structure property relationships of N-acylsulfonamides and related bioisosteres
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The N-acylsulfonamide functional group is a feature of the pharmacophore of several biologically active molecules, including marketed drugs. Although this acidic moiety presents multiple points of attachments that could be exploited to introduce structural diversification, depending on the circumstances, the replacement of the functional group itself with a suitable surrogate, or bioisostere, may be desirable. A number of N-acylsulfonamide bioisosteres have been developed over the years that provide opportunities to modulate both structure and physicochemical properties of this important structural motif. To enable an assessment of the relative impact on physicochemical properties that these replacements may have compared to the N-acylsulfonamide group, we conducted a structure-property relationship study based on matched molecular pairs, in which the N-acylsulfonamide moiety of common template reference structures is replaced with a series of bioisosteres. The data presented, which include an assessment of relative changes in acidity, permeability, lipophilicity and intrinsic solubility, provides a basis for informed decisions when deploying N-acylsulfonamides, or surrogates thereof, in analog design.
- Ballatore, Carlo,Brancale, Andrea,Francisco, Karol R.,Kozlowski, Marisa C.,Paniak, Thomas J.,Varricchio, Carmine
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- SUBSTITUTED FURO[3,2-D]PYRIMIDINES AND USES THEREOF
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The present disclosure provides compounds that are inhibitors of PIKfyve and/or PI3 kinases, and are therefore useful for the treatment of neurological diseases treatable by inhibition of PIKfyve and/or PI3 kinases. Also provided are pharmaceutical compositions containing such compounds, and methods of treatment of neurological diseases using such compounds.
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Paragraph 0200-0201
(2021/09/17)
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- HETEROARYL PYRIDONE AND AZA-PYRIDONE COMPOUNDS AS INHIBITORS OF BTK ACTIVITY
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Heteroaryl pyridone and aza-pyridone compounds of Formula I are provided, where one or two of X, X, and Xare N, and including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for inhibiting Btk kinase, and for treating immune disorders such as inflammation mediated by Btk kinase. Methods of using compounds of Formula I foranddiagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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Paragraph 1209; 1210
(2015/11/16)
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- Structure-activity relationship study of E6 as a novel necroptosis inducer
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Necroptosis inducers represent a promising potential treatment for drug-resistant cancer. We herein describe the structure modification of E6, which was identified recently as a potent and selective necroptosis inducer. The studies described herein demonstrate for the first time that functionalized biphenyl derivatives possess necroptosis inducer activity. Furthermore, these studies have led to the identification of two promising compounds (5h and 5j) that can be used for further optimization studies as well as mechanism of action investigations.
- Mou, Jianfeng,Park, Ann,Cai, Yu,Yuan, Junying,Yuan, Chengye
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supporting information
p. 3057 - 3061
(2015/06/22)
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- Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1, 1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea hydrochloride (CEP-32496), a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) V600E
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The Ras/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway plays a central role in the regulation of cell growth, differentiation, and survival. Expression of mutant BRAFV600E results in constitutive activation of the MAPK pathway, which can lead to uncontrolled cellular growth. Herein, we describe an SAR optimization campaign around a series of quinazoline derived BRAFV600E inhibitors. In particular, the bioisosteric replacement of a metabolically sensitive tert-butyl group with fluorinated alkyl moieties is described. This effort led directly to the identification of a clinical candidate, compound 40 (CEP-32496). Compound 40 exhibits high potency against several BRAFV600E-dependent cell lines and selective cytotoxicity for tumor cell lines expressing mutant BRAFV600E versus those containing wild-type BRAF. Compound 40 also exhibits an excellent PK profile across multiple preclinical species. In addition, significant oral efficacy was observed in a 14-day BRAFV600E-dependent human Colo-205 tumor xenograft mouse model, upon dosing at 30 and 100 mg/kg BID.
- Rowbottom, Martin W.,Faraoni, Raffaella,Chao, Qi,Campbell, Brian T.,Lai, Andiliy G.,Setti, Eduardo,Ezawa, Maiko,Sprankle, Kelly G.,Abraham, Sunny,Tran, Lan,Struss, Brian,Gibney, Michael,Armstrong, Robert C.,Gunawardane, Ruwanthi N.,Nepomuceno, Ronald R.,Valenta, Ianina,Hua, Helen,Gardner, Michael F.,Cramer, Merryl D.,Gitnick, Dana,Insko, Darren E.,Apuy, Julius L.,Jones-Bolin, Susan,Ghose, Arup K.,Herbertz, Torsten,Ator, Mark A.,Dorsey, Bruce D.,Ruggeri, Bruce,Williams, Michael,Bhagwat, Shripad,James, Joyce,Holladay, Mark W.
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experimental part
p. 1082 - 1105
(2012/04/04)
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- HETEROCYCLIC COMPOUNDS CONTAINING A PYRROLOPYRIDINE OR BENZIMIDAZOLE CORE
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The present invention relates to compounds of Formula (I) and pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5 and n are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.
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Page/Page column 77-78
(2011/06/26)
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- HETEROCYCLIC COMPOUNDS CONTAINING AN INDOLE CORE
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Disclosed are novel compounds which inhibit RSK, methods of making such compounds and pharmaceutical compositions comprising such compounds. Also disclosed are methods of treating RSK2 regulated disorders using compounds of the invention.
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Page/Page column 93
(2011/06/26)
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- Pyridyloxyindoles Inhibitors of VEGF-R2 and Use Thereof for Treatment of Disease
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The invention relates to novel organic compounds of formula (I), and their use in the treatment of the animal or human body, to pharmaceutical compositions comprising a compound of formula I and to the use of a compound of formula I for the preparation of pharmaceutical compositions for use in the treatment of protein kinase dependent diseases, especially of proliferative diseases, such as in the treatment of tumour diseases and ocular neovascular diseases.
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Page/Page column 62
(2010/06/22)
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- Amino-substituted pyrimidinyl derivatives and methods of use
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The invention encompasses compounds, analogs, prodrugs and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions, uses and methods for prophylaxis and treatment of cancer.
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- Allenes. Part 42. Nucleophilic Addition of Hydroxylamine to Allenic and Acetylenic Nitriles; Synthesis of 3-Alkyl-5-amino, 5-Amino-3-phenyl, and 3-Amino-5-phenyl-isoxazoles
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Hydroxylamine adds to allenic nitriles to give 3-alkyl-5-aminoisoxazoles in excellent yield.Hydroxyacetylenic nitriles similarly give 5-amino-3-(1-hydroxyalkyl)isoxazoles.Phenylpropynenitrile under varying conditions of temperature and solvent yields mainly 5-amino-3-phenylisoxazole with varying amounts of 3-amino-5-phenylisoxazole as a by-product.
- Fomum, Z. Tanee,Asobo, P. Forsche,Landor, Stephen R.,Landor, Phyllis D.
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p. 1079 - 1083
(2007/10/02)
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