- ALTERNATE PROCESSES FOR THE PREPARATION OF OMECAMTIV MECARBIL
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Aspects of the present application relate to process for the preparation of Omecamtiv mecarbil and salts thereof. Specific aspects relate to novel urea intermediate, preparative process thereof and its use in the preparation of Omecamtiv mecarbil and salts thereof. The improved process for the preparation of Omecamtiv mecarbil are industrially viable.
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- From off-to on-target: New BRAF-inhibitor-template-derived compounds selectively targeting mitogen activated protein kinase kinase 4 (MKK4)
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The mitogen-activated protein kinase (MAP) kinase 4 (MKK4) was found to be a major regulator of liver regeneration and could be a valuable drug target addressing liver related diseases by restoring its intrinsic regenerative capacity. We report on the synthesis and optimization of novel MKK4 inhibitors following a target-hopping strategy from the FDA-approved BRAFV600E inhibitor PLX4032 (8). Applying an iterative multi-parameter optimization process we carved out essential structural features yielding in compounds with a low nanomolar affinity for MKK4 and excellent selectivity profiles against the main off-targets MKK7 and JNK1, which, upon relevant inhibition, would totally abrogate the pro-regenerative effect of MKK4 inhibition, as well as against the off-targets MAP4K5, ZAK and BRAF with selectivity factors ranging from 40 to 430 for our best-balanced compounds 70 and 73.
- Kl?vekorn, Philip,Pfaffenrot, Bent,Juchum, Michael,Selig, Roland,Albrecht, Wolfgang,Zender, Lars,Laufer, Stefan A.
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- Synthesis method of anti-cancer drug intermediate methyl 2-fluoro-3-aminobenzoate
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The invention discloses a synthetic method of 2-fluoro-3-methyl aminobenzoate, and belongs to the technical field of synthesis of medical intermediates. According to the method, 2, 6-dichlorobenzoic acid is taken as a raw material, 2, 6-dichloro-3-nitrobe
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Paragraph 0052-0055
(2020/07/13)
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- PROTEIN KINASE INHIBITORS FOR PROMOTING LIVER REGENERATION OR REDUCING OR PREVENTING HEPATOCYTE DEATH
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The invention relates to MKK4 (mitogen-activated protein kinase 4) and their use in promoting liver regeneration or reducing or preventing hepatocyte death. The MKK4 inhibitors selectively inhibit protein kinase MKK4 over protein kinases JNK and MKK7.
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Page/Page column 32; 53
(2018/08/12)
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- Thiazole kinase inhibitors
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The invention belongs to the technical field of medicine, and particularly relates to a thiazole kinase inhibitor shown as a general formula (I), and pharmaceutically acceptable salts or stereisomers thereof, wherein R1, R2, R3, R4, m, n and p are defined
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- PROCESSES FOR THE PREPARATION OF DABRAFENIB
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A process for the preparation of dabrafenib and pharmaceutically acceptable salts thereof comprising the step of reacting formula-Ill (wherein X is a leaving group) with formamide in the presence of a base to get formula-ll
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Page/Page column 8
(2016/05/24)
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- Discovery of dabrafenib: A selective inhibitor of Raf Kinases with antitumor activity against B-Raf-driven tumors
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Hyperactive signaling of the MAP kinase pathway resulting from the constitutively active B-RafV600E mutated enzyme has been observed in a number of human tumors, including melanomas. Herein we report the discovery and biological evaluation of GSK2118436, a selective inhibitor of Raf kinases with potent in vitro activity in oncogenic B-Raf-driven melanoma and colorectal carcinoma cells and robust in vivo antitumor and pharmacodynamic activity in mouse models of B-RafV600E human melanoma. GSK2118436 was identified as a development candidate, and early clinical results have shown significant activity in patients with B-Raf mutant melanoma.
- Rheault, Tara R.,Stellwagen, John C.,Adjabeng, George M.,Hornberger, Keith R.,Petrov, Kimberly G.,Waterson, Alex G.,Dickerson, Scott H.,Mook, Robert A.,Laquerre, Sylvie G.,King, Alastair J.,Rossanese, Olivia W.,Arnone, Marc R.,Smitheman, Kimberly N.,Kane-Carson, Laurie S.,Han, Chao,Moorthy, Ganesh S.,Moss, Katherine G.,Uehling, David E.
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p. 358 - 362
(2013/05/09)
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- BENZENE SULFONAMIDE THIAZOLE AND OXAZOLE COMPOUNDS
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The present invention provides thiazole sulfonamide and oxazole sulfonamide compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.
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- Planar macrocyclic fluoropentamers as supramolecular organogelators
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Despite their great diversities, 2D-shaped macrocycles that can serve as the organogelators have been surprisingly rare; two planar macrocyclic fluoropentamers designed by us were highly able to gelate organic solvents, largely derived from their strong tendency to form 1D stacked fibrillar structures stabilized by both interplanar H-bonds and π-π stacking forces.
- Ren, Changliang,Xu, Shengyu,Xu, Jun,Chen, Hongyu,Zeng, Huaqiang
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p. 3840 - 3843
(2011/09/19)
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- Crystallographic realization of the mathematically predicted densest all-pentagon packing lattice by C5-symmetric "sticky" fluoropentamers
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Regular pentagonal adhesive tiles were obtained by designing a cyclic fluoropentamer with an internal CF...HN H-bonded network and "sticky" edges that can glue the molecules together through intermolecular CArH...O=C H bonds. In the crystal they form the mathematically predicted densest all-pentagon 2D lattice with a packing density of 0.921 (see picture). Copyright
- Ren, Changliang,Zhou, Feng,Qin, Bo,Ye, Ruijuan,Shen, Sheng,Su, Haibin,Zeng, Huaqiang
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p. 10612 - 10615
(2012/01/04)
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- HETEROARYL COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
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The present invention provides compounds of Formula (I): wherein R1, R2, R3, and X are as defined herein. The compounds of Formula (I) and pharmaceutical compositions thereof are useful for the treatment of cancer, and B-
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- COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS THEREFOR
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Compounds and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described. In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof are active on at least one Raf protein kinase. In certain aspects and embodiments, the described compounds are active in inhibiting proliferation of a Ras mutant cell line. Also described are methods of use thereof to treat diseases and conditions, including diseases and conditions associated with activity of B-Raf V600E mutant protein kinase, including melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma, colorectal cancer, thyroid cancer, lung cancer, ovarian cancer, prostate cancer, liver cancer, gallbladder cancer, gastrointestinal stromal tumors, biliary tract cancer, and cholangiocarcinoma. Also described are methods of use thereof to treat diseases and conditions, including diseases and conditions associated with activity of c-Raf-1 protein kinase, including acute pain, chronic pain or polycystic kidney disease.
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- THIAZOLE SULFONAMIDE AND OXAZOLE SULFONAMIDE KINASE INHIBITORS
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The present invention provides thiazole sulfonamide and oxazole sulfonamide compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents
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Page/Page column 162-163
(2010/10/03)
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- Benzene Sulfonamide Thiazole and Oxazole Compounds
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The present invention provides thiazole sulfonamide and oxazole sulfonamide compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.
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