- Matrix Metalloproteinase 13 Inhibitors for Modulation of Osteoclastogenesis: Enhancement of Solubility and Stability
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Matrix metalloproteinase 13 (MMP-13) activity has been correlated to breast cancer bone metastasis. It has been proposed that MMP-13 contributes to bone metastasis through the promotion of osteoclastogenesis. To explore the mechanisms of MMP-13 action, we previously described a highly efficacious and selective MMP-13 inhibitor, RF036. Unfortunately, further pursuit of RF036 as a probe of MMP-13 in vitro and in vivo activities was not practical due to the limited solubility and stability of the inhibitor. Our new study has explored replacing the RF036 backbone sulfur atom and terminal methyl group to create inhibitors with more favorable pharmacokinetic properties. One compound, designated inhibitor 3, in which the backbone sulfur and terminal methyl group of RF036 were replaced by nitrogen and oxetane, respectively, had comparable activity, selectivity, and membrane permeability to RF036, while exhibiting greatly enhanced solubility and stability. Inhibitor 3 effectively inhibited MMP-13-mediated osteoclastogenesis but spared collagenolysis, and thus represents a next-generation MMP-13 probe applicable for in vivo studies of breast cancer metastasis.
- Knapinska, Anna M.,Singh, Chandani,Drotleff, Gary,Blanco, Daniela,Chai, Cedric,Schwab, Jason,Herd, Anu,Fields, Gregg B.
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supporting information
p. 1133 - 1142
(2021/01/29)
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- STAT DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 00673; 00674
(2021/09/26)
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- FERROPTOSIS INHIBITORS–DIARYLAMINE PARA-ACETAMIDES
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Provided are compounds that inhibit ferroptosis activity, or modulate or inhibit a disease associated with ferroptosis dysregulation, such as neuropathy, ischemia reperfusion injury, acute kidney failure and cancer, including corresponding sulfonamides, and pharmaceutically acceptable salts, hydrates and stereoisomers thereof. The compounds are employed in pharmaceutical compositions, and methods of making and use, including treating a person in need thereof with an effective amount of the compound or composition, and detecting a resultant improvement in the person's health or condition.
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Paragraph 01607-01608
(2021/09/11)
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- A Facile Synthesis of Ligands for the von Hippel-Lindau E3 Ligase
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The proteolysis-targeting chimeras (PROTACs) have become an integral part of different stages of drug discovery. This growing field, therefore, benefits from advancements in all segments of the design of these compounds. Herein, an efficient and optimized synthetic protocol to various von Hippel-Lindau (VHL) ligands is presented, which enables easy access to multigram quantities of these essential PROTAC building blocks. Moreover, the elaborated synthesis represents a straightforward approach to further explore the chemical space of VHL ligands.
- Bricelj, Ale?a,Gütschow, Michael,Schnakenburg, Gregor,Sosi?, Izidor,Steinebach, Christian,Voell, Sabine Anna,Vu, Lan Phuong
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p. 2521 - 2527
(2020/09/07)
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- PYRROLE AND PYRAZOLE COMPOUNDS AND METHODS OF USE THEREOF
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The disclosure relates to anti-cancer compounds derived from nuclear steroid receptor binders, to products containing the same, as well as to methods of their use and preparation. The present disclosure provides compounds having hormone receptor antagonis
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Page/Page column 78
(2020/06/19)
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- Benzoquinone derivative, pharmaceutical composition, and applications thereof
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The invention discloses a benzoquinone derivative, a pharmaceutical composition, and applications thereof. According to the invention, the benzoquinone derivative (I), and the stereoisomer or the pharmaceutically acceptable salt thereof possess a structure disclosed in the invention. The benzoquinone derivative possesses excellent inhibition effect on STAT3 level both in vivo and in vitro, and further, the benzoquinone derivative is capable of inhibiting balling capacity of cancer cells.
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Paragraph 0266-0269
(2019/11/29)
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- Structure–Activity Relationship Studies on (R)-PFI-2 Analogues as Inhibitors of Histone Lysine Methyltransferase SETD7
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SETD7 is a histone H3K4 lysine methyltransferase involved in human gene regulation. Aberrant expression of SETD7 has been associated with various diseases, including cancer. Therefore, SETD7 is considered a good target for the development of new epigenetic drugs. To date, few selective small-molecule inhibitors have been reported that target SETD7, the most potent being (R)-PFI-2. Herein we report structure–activity relationship studies on (R)-PFI-2 and its analogues. A library of 29 structural analogues of (R)-PFI-2 was synthesized and evaluated for inhibition of recombinantly expressed human SETD7. The key interactions were found to be a salt bridge and a hydrogen bond formed between (R)-PFI-2′s NH2+ group and SETD7′s Asp256 and His252 residue, respectively.
- Lenstra, Danny C.,Damen, Eddy,Leenders, Ruben G. G.,Blaauw, Richard H.,Rutjes, Floris P. J. T.,Wegert, Anita,Mecinovi?, Jasmin
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supporting information
p. 1405 - 1413
(2018/07/29)
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- NOVEL ANTIBIOTICS AND METHODS OF USING SAME
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The present invention includes novel 3,6-diazabicyclo[3.1.1]heptane antibiotic compounds and any salts or solvates thereof. The present invention further includes methods of preparing such compounds, and methods of treating bacterial infection in a subjec
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Page/Page column 62
(2018/05/16)
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- Development of matrix metalloproteinase-13 inhibitors – A structure-activity/structure-property relationship study
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A structure-activity/structure-property relationship study based on the physicochemical as well as in vitro pharmacokinetic properties of a first generation matrix metalloproteinase (MMP)-13 inhibitor (2) was undertaken. After systematic variation of inhi
- Fuerst, Rita,Yong Choi, Jun,Knapinska, Anna M.,Smith, Lyndsay,Cameron, Michael D.,Ruiz, Claudia,Fields, Gregg B.,Roush, William R.
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p. 4984 - 4995
(2018/09/27)
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- HETEROARYL COMPOUNDS AS BTK INHIBITORS AND USES THEREOF
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The present invention relates to imidazo pyridine compounds, and pharmaceutically acceptable compositions thereof, useful as BTK inhibitors.
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Paragraph 0381; 0396
(2016/05/02)
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- TrkA KINASE INHIBITORS, COMPOSITIONS AND METHODS THEREOF
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The present invention is directed to substituted indole compounds of formula (I) which are tropomyosin-related kinase (Trk) family protein kinase inhibitors, and hence are useful in the treatment of pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, adisease, disorder, injury, or malfunction relating to dysmyelination or demyelination or a disease or disorder associated with abnormal activities of nerve growth factor (NGF) receptor TrkA.
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Page/Page column 79
(2016/05/02)
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- 2-PYRIDONE ANTIMICROBIAL COMPOSITIONS
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Described are a series of 2-pyridone compounds as a potent and selective new class of type II topoisomerase inhibitors with broad-spectrum antimicrobial activity having the general formula (I); where R1, R2, X, and Y are defined herein Such compounds can
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Paragraph 0381-0382
(2016/08/23)
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- IMIDAZO [1, 2 - B] PYRIDAZINE - BASED COMPOUNDS, COMPOSITIONS COMPRISING THEM, AND USES THEREOF
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Imidazo[1,2-b]pyridazine-based compounds of the formula (I): are disclosed, wherein R1, R2 and R3 are defined herein. Compositions comprising the compounds and methods of their use to treat, manage and/or prevent diseases and disorders mediated by mediated by adaptor associated kinase 1 activity are also disclosed.
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Page/Page column 47
(2013/09/26)
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- ANTIMICROBIAL 4-OXOQUINOLIZINES
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This invention provides novel 4-oxoquinolizine compounds and their uses for a series of broad-spectrum antibiotics having no cross-resistance to existing or emerging classes of antibiotics. In addition the novel 4-oxoquinolizine compounds are useful again
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Page/Page column 126
(2012/08/27)
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