- ALPHA-5 BETA-1 INHIBITORS
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The disclosure provides, inter alia, alpha-5 beta-1 inhibitors, pharmaceutical compositions comprising alpha-5 beta-1 inhibitors, methods for treating diseases using alpha-5 beta-1 inhibitors, and processes for making alpha-5 beta-1 inhibitors.
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Paragraph 0759; 0803-0805
(2021/06/11)
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- Integrated Synthesis Using Isothiocyanate-Substituted Aryllithiums by Flow Chemistry
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The isothiocyanate (NCS) group is an attractive functional group in the field of organic and pharmaceutical chemistry. It can be transformed into other heteroatomic functional groups. It usually acts as the inductive group of biological activity and has also been traditionally used as the fluorescent-labeling reagent. However, it is not compatible with strong bases. When the NCS group is at para position in halobenzenes, it generally undergoes nucleophilic additions upon reaction with strong bases. To the best of our knowledge, there is currently no general methodology for the formation and reactions of NCS-functionalized aryllithiums for meta and para substituents. Herein, we report the continuous-flow generation of NCS-substituted aryllithiums from the corresponding haloarenes via a selective halogen-lithium exchange reaction and its reaction with various electrophiles to yield NCS-containing products. We also achieved an integrated synthesis through sequential reactions of the NCS-containing compounds with additional nucleophiles using the continuous-flow reactors.
- Lee, Hyune-Jea,Torii, Daiki,Jeon, Yongju,Yoshida, Jun-Ichi,Kim, Heejin
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supporting information
p. 1899 - 1902
(2020/09/11)
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- Inhibitors of the Diadenosine Tetraphosphate Phosphorylase Rv2613c of Mycobacterium tuberculosis
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The intracellular concentration of diadenosine tetraphospate (Ap4A) increases upon exposure to stress conditions. Despite being discovered over 50 years ago, the cellular functions of Ap4A are still enigmatic. If and how the varied Ap4A is a signal and involved in the signaling pathways leading to an appropriate cellular response remain to be discovered. Because the turnover of Ap4A by Ap4A cleaving enzymes is rapid, small molecule inhibitors for these enzymes would provide tools for the more detailed study of the role of Ap4A. Here, we describe the development of a high-throughput screening assay based on a fluorogenic Ap4A substrate for the identification and optimization of small molecule inhibitors for Ap4A cleaving enzymes. As proof-of-concept we screened a library of over 42, 000 compounds toward their inhibitory activity against the Ap4A phosphorylase (Rv2613c) of Mycobacterium tuberculosis (Mtb). A sulfanylacrylonitril derivative with an IC50 of 260 ± 50 nM in vitro was identified. Multiple derivatives were synthesized to further optimize their properties with respect to their in vitro IC50 values and their cytotoxicity against human cells (HeLa). In addition, we selected two hits to study their antimycobacterial activity against virulent Mtb to show that they might be candidates for further development of antimycobacterial agents against multidrug-resistant Mtb.
- G?tz, Kathrin H.,Hacker, Stephan M.,Mayer, Daniel,Dürig, Jan-Niklas,Stenger, Steffen,Marx, Andreas
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p. 2682 - 2689
(2017/10/27)
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- Methyl 3-((6-methoxy-1,4-dihydroindeno[1,2-c]pyrazol-3-yl)amino)benzoate (GN39482) as a tubulin polymerization inhibitor identified by morphobase and chemproteobase profiling methods
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A series of indenopyrazoles was synthesized from the corresponding indanones and phenyl isothiocyanates in two steps. Among the compounds synthesized, methyl 3-((6-methoxy-1,4-dihydroindeno[1,2-c]pyrazol-3-yl)amino)benzoate 6m (GN39482) was found to posse
- Minegishi, Hidemitsu,Futamura, Yushi,Fukashiro, Shinji,Muroi, Makoto,Kawatani, Makoto,Osada, Hiroyuki,Nakamura, Hiroyuki
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p. 4230 - 4241
(2015/06/08)
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- Selectively targeting T- and B-cell lymphomas: A benzothiazole antagonist of α4β1integrin
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Current cancer chemotherapeutic agents clinically deployed today are designed to be indiscriminately cytotoxic, however, achieving selective targeting of cancer malignancies would allow for improved diagnostic and chemotherapeutic tools. Integrin α4β1, a heterodimeric cell surface receptor, is believed to have a low- affinity conformation in resting normal lymphocytes and an activated high-affinity conformation in cancerous cells, specifically T- and B-cell lymphomas. This highly attractive yet poorly understood receptor has been selectively targeted with the bisaryl urea peptidomimetic antagonist i. However, concerns regarding its preliminary pharmacokinetic (PK) profile provided an impetus to change the pharmacophore from a bisaryl urea to a 2-arylaminobenzothiazole moiety, resulting in an analogue with improved physicochemical properties, solubility, and kidney:tumor ratio while maintaining potency (6;IC50 = 53 pM). The results presented herein utilized heterocyclic and solid-phase chemistry, cell adhesion assay, and in vivo optical imaging using the cyanine dye Cy5.5 conjugate.
- Carpenter, Richard D.,Andrei, Mirela,Aina, Olulanu H.,Lau, Edmond Y.,Lightstone, Felice C.,Liu, Ruiwu,Lam, Kit S.,Kurth, Mark J.
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experimental part
p. 14 - 19
(2009/11/30)
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- HETEROCYCLIC LIGANDS FOR INTEGRIN IMAGING AND THERAPY
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The present invention provides α 4?1 integrin ligands that display high binding affinity, specificity, and stability. The ligands comprise a peptide having n independently selected amino acids, wherein at least one amino acid is an unnatural amino acid or a D-amino acid, and wherein n is an integer of from 3 to 20. Methods are provided for administering the ligands for treating cancer, inflammatory diseases, and autoimmune diseases. Also provided are methods for administering the ligands for imaging a tumor, organ, or tissue in a subject.
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Page/Page column 38
(2010/11/30)
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- Highly potent, water soluble benzimidazole antagonist for activated α4β1 integrin
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The cell surface receptor α4β1 integrin, activated constitutively in lymphoma, can be targeted with the bisaryl urea peptidomimetic antagonist 1 (LLP2A). However, concerns on its preliminary pharmacokinetic (PK) profile provided an impetus to change the pharmacophore from a bisaryl urea to a 2-arylaminobenzimidazole moiety, resulting in improved solubility while maintaining picomolar potency [5 (KLCA4); IC50 = 305 pM]. With exceptional solubility, this finding has the potential for improving PK to help diagnose and treat lymphomas.
- Carpenter, Richard D.,Andrei, Mirela,Lau, Edmond Y.,Lightstone, Felice C.,Liu, Ruiwu,Lam, Kit S.,Kurth, Mark J.
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p. 5863 - 5867
(2008/04/05)
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