- Evaluation of anti-depressant effects of phthalazinone-based triple-acting small molecules against 5-HT2A, 5-HT2C, and the serotonin transporter
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Development of highly effective, safe, and fast-acting anti-depressants is urgently required for the treatment of major depressive disorder. It has been suggested that targeting 5-HT2A and 5-HT2C in addition to inhibition of serotonin reuptake may be beneficial in generating anti-depressant agents with better pharmacology and less adverse effects. We have developed phthalazinone-based compounds that potently bind to 5-HT2A, 5-HT2C, and the serotonin transporter. The representative compounds 11j and 11l displayed strong binding affinities against these targets, and showed favorable toxicity profiles as determined by hERG binding and CYP inhibition assays. Furthermore, these compounds presented promising anti-depressant effects comparable to fluoxetine and also synergistic effects with fluoxetine in forced swimming test, which implicates these compounds can be developed to help the treatment of major depressive disorder.
- Kim, Jihye,Cha, Eunji,Park, Woo Kyu,Lee, Hye Yeon,Lim, Sang Min,Kim, Hak Joong,Pae, Ae Nim
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- Targeting of Fumarate Hydratase from Mycobacterium tuberculosis Using Allosteric Inhibitors with a Dimeric-Binding Mode
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With the growing worldwide prevalence of antibiotic-resistant strains of tuberculosis (TB), new targets are urgently required for the development of treatments with novel modes of action. Fumarate hydratase (fumarase), a vulnerable component of the citric acid cycle in Mycobacterium tuberculosis (Mtb), is a metabolic target that could satisfy this unmet demand. A key challenge in the targeting of Mtb fumarase is its similarity to the human homolog, which shares an identical active site. A potential solution to this selectivity problem was previously found in a high-throughput screening hit that binds in a nonconserved allosteric site. In this work, a structure-activity relationship study was carried out with the determination of further structural biology on the lead series, affording derivatives with sub-micromolar inhibition. Further, the screening of this series against Mtb in vitro identified compounds with potent minimum inhibitory concentrations.
- Whitehouse, Andrew J.,Libardo, M. Daben J.,Kasbekar, Monica,Brear, Paul D.,Fischer, Gerhard,Thomas, Craig J.,Barry, Clifton E.,Boshoff, Helena I. M.,Coyne, Anthony G.,Abell, Chris
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p. 10586 - 10604
(2019/10/16)
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- NOVEL IL-2/IL-15 RECEPTOR ANTAGONIST COMPOUNDS AND USES THEREOF FOR THE TREATMENT OF AUTOIMMUNE AND INFLAMMATORY DISEASES OR GRAFT REJECTION
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Novel IL-2/IL-15 Receptor antagonist compounds and uses thereof for the treatment of autoimmune and inflammatory diseases or graft rejection Novel IL-2/IL-15 Receptor antagonist compounds and uses thereof for the treatment of autoimmune and inflammatory diseases or graft rejection. The invention relates to a compound of general formula (1) wherein X represents O, S or NR 4, wherein R4 is alkyl; A is selected from S, SO, SO2, NH and O; Y represents (CR5R6)n or (CR5 R6 O)n, wherein R5 and R6 identical or different are H or alkyl and n represents an integer from 1 to 15; R1 represents a 5 to 10 membered aromatic or non-aromatic mono-or bicyclic, 1 optionally bridged ring, R2 is C1-C4 alkyl; R3 is H or alkyl; p is 0 or 1; or a pharmaceutically acceptable salt thereof. The compounds of the invention are inhibitors of the interactions of IL-2/15 to IL-2/15Rβand hence useful in the treatment of an autoimmune or an inflammatory diseases and graft rejection.
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- METHODS AND COMPOSITIONS FOR INHIBITING CNKSR1
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Embodiments include compositions and methods of inhibiting CNKSR1 and methods of identifying inhibitors of CNKSR1.
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- Phthalazinone inhibitors of inosine-5′-monophosphate dehydrogenase from Cryptosporidium parvum
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Cryptosporidium parvum (Cp) is a potential biowarfare agent and major cause of diarrhea and malnutrition. This protozoan parasite relies on inosine 5′-monophosphate dehydrogenase (IMPDH) for the production of guanine nucleotides. A CpIMPDH-selective N-aryl-3,4-dihydro-3-methyl-4-oxo-1- phthalazineacetamide inhibitor was previously identified in a high throughput screening campaign. Herein we report a structure-activity relationship study for the phthalazinone-based series that resulted in the discovery of benzofuranamide analogs that exhibit low nanomolar inhibition of CpIMPDH. In addition, the antiparasitic activity of select analogs in a Toxoplasma gondii model of C. parvum infection is also presented.
- Johnson, Corey R.,Gorla, Suresh Kumar,Kavitha, Mandapati,Zhang, Minjia,Liu, Xiaoping,Striepen, Boris,Mead, Jan R.,Cuny, Gregory D.,Hedstrom, Lizbeth
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p. 1004 - 1007
(2013/03/13)
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- Discovery of thiazolyl-phthalazinone acetamides as potent glucose uptake activators via high-throughput screening
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With the aim to discover orally active small molecules that stimulate glucose uptake, high throughput screening of a library of 5000 drug-like compounds was conducted in differentiated skeletal muscle cells in presence of insulin. N-Substituted phthalazinone acetamide was identified as a potential glucose uptake modulator. Several novel derivatives were synthesized to establish structure activity relationships. Identified lead thiazolyl- phthalazinone acetamide (7114863) increased glucose uptake (EC50 of 0.07 ± 0.02 μM) in differentiated skeletal muscle cells in presence of insulin. Furthermore, 7114863 was superior to rosiglitazone under similar experimental conditions without inducing PPAR-γ agonist activity thus making it a very interesting scaffold.
- Agrawal, Madhavi,Kharkar, Prashant,Moghe, Sonali,Mahajan, Tushar,Deka, Vaishali,Thakkar, Chandni,Nair, Amrutha,Mehta, Chirag,Bose, Julie,Kulkarni-Almeida, Asha,Bhedi, Dilip,Vishwakarma, Ram A.
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p. 5740 - 5743
(2013/10/01)
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