- Synthesis and preliminary biological evaluation at the glycineB site of (+)- and (-)-3-oxetanylglycine, novel non-proteinogenic amino acids
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Two novel non-proteinogenic amino acids, (+)- and (-)-3-oxetanylglycine were synthesized and evaluated for their ability to diplace [3H]-glycine from the glycine site of the NMDA receptor complex. The lack of activity of these compounds at conc
- Del Carmen Teran Moldes, Maria,Costantino, Gabriele,Marinozzi, Maura,Pellicciari, Roberto
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- Improving the metabolic stability of antifungal compounds based on a scaffold hopping strategy: Design, synthesis, and structure-activity relationship studies of dihydrooxazole derivatives
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L-amino alcohol derivatives exhibited high antifungal activity, but the metabolic stability of human liver microsomes in vitro was poor, and the half-life of optimal compound 5 was less than 5 min. To improve the metabolic properties of the compounds, the scaffold hopping strategy was adopted and a series of antifungal compounds with a dihydrooxazole scaffold was designed and synthesized. Compounds A33-A38 substituted with 4-phenyl group on dihydrooxazole ring exhibited excellent antifungal activities against C. albicans, C. tropicalis and C. krusei, with MIC values in the range of 0.03–0.25 μg/mL. In addition, the metabolic stability of compounds A33 and A34 in human liver microsomes in vitro was improved significantly, with the half-life greater than 145 min and the half-life of 59.1 min, respectively. Moreover, pharmacokinetic studies in SD rats showed that A33 exhibited favourable pharmacokinetic properties, with a bioavailability of 77.69%, and half-life (intravenous administration) of 9.35 h, indicating that A33 is worthy of further study.
- Cheng, Maosheng,Su, Xin,Sun, Nannan,Sun, Yin,Tian, Linfeng,Yin, Wenbo,Zhang, Chu,Zhao, Dongmei,Zhao, Liyu,Zhao, Shizhen,Zheng, Yang
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- Construction of a Shape-Diverse Fragment Set: Design, Synthesis and Screen against Aurora-A Kinase
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Historically, chemists have explored chemical space in a highly uneven and unsystematic manner. As an example, the shape diversity of existing fragment sets does not generally reflect that of all theoretically possible fragments. To assess experimentally the added value of increased three dimensionality, a shape-diverse fragment set was designed and collated. The set was assembled by both using commercially available fragments and harnessing unified synthetic approaches to sp3-rich molecular scaffolds. The resulting set of 80 fragments was highly three-dimensional, and its shape diversity was significantly enriched by twenty synthesised fragments. The fragment set was screened by high-throughput protein crystallography against Aurora-A kinase, revealing four hits that targeted the binding site of allosteric regulators. In the longer term, it is envisaged that the fragment set could be screened against a range of functionally diverse proteins, allowing the added value of more shape-diverse screening collections to be more fully assessed.
- Zhang, Rong,McIntyre, Patrick J.,Collins, Patrick M.,Foley, Daniel J.,Arter, Christopher,von Delft, Frank,Bayliss, Richard,Warriner, Stuart,Nelson, Adam
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supporting information
p. 6831 - 6839
(2019/05/10)
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- CERAMIDE GALACTOSYLTRANSFERASE INHIBITORS FOR THE TREATMENT OF DISEASE
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Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with the enzyme ceramide galactosyltransferase (CGT), such as, for example, lysosomal storage diseases. Examples of lysosomal storage diseases include, for example, Krabbe disease and Metachromatic Leukodystrophy.
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Paragraph 0001021; 0001022
(2018/01/17)
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- FUSED MORPHOLINOPYRIMIDINES AND METHODS OF USE THEREOF
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The present disclosure relates to Fused Morpholinopyrimidines, pharmaceutical compositions comprising an effective amount of a Fused Morpholinopyrimidine and methods for using a Fused Morpholinopyrimidine in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine.
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Paragraph 1172
(2017/05/14)
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- FUSED MORPHOLINOPYRIMIDINES AND METHODS OF USE THEREOF
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The present disclosure relates to Fused Morpholinopyrimidines, pharmaceutical compositions comprising an effective amount of a Fused Morpholinopyrimidine and methods for using a Fused Morpholinopyrimidine in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine.
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Paragraph 0862
(2015/08/03)
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- The discovery of potent nonstructural protein 5A (NS5A) inhibitors with a unique resistance profile - Part 2
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In ongoing studies towards novel hepatitis C virus (HCV) therapeutics, inhibitors of nonstructural protein 5A (NS5A) were evaluated. Specifically, starting from previously reported lead compounds, peripheral substitution patterns of a series of biaryl-linked pyrrolidine NS5A replication complex inhibitors were probed and structure-activity relationships were elucidated. Using molecular modelling and a supercritical fluid chromatographic (SFC) technique, intramolecular H-bonding and peripheral functional group topology were evaluated as key determinants of activity and membrane permeability. The novel compounds exhibited retained potency as compared with the lead compounds, and also showed promising results against a panel of resistance viruses. Together, the results of the study take us a step closer towards understanding the potency of daclatasvir, a clinical candidate upon which the compounds were based, and to designing improved analogues as second-generation antiviral agents targeting NS5A. Refining the resistance: An investigation into the anti-hepatitis C virus (HCV) replicon activity of a series of biaryl-linked prolinamide NS5A inhibitors explored intramolecular H-bonding and peripheral functional group topology as key determinants of activity and membrane permeability. Studies of several peripheral group molecular designs resulted in compounds with improved aqueous solubility and a unique resistance profile.
- Wakenhut, Florian,Tran, Thien Duc,Pickford, Chris,Shaw, Stephen,Westby, Mike,Smith-Burchnell, Caroline,Watson, Lesa,Paradowski, Michael,Milbank, Jared,Stonehouse, David,Cheung, Kathy,Wybrow, Robert,Daverio, Felice,Crook, Samuel,Statham, Keith,Leese, David,Stead, Darren,Adam, Fiona,Hay, Duncan,Roberts, Lee R.,Chiva, Jean-Yves,Nichols, Carly,Blakemore, David C.,Goetz, Gilles H.,Che, Ye,Gardner, Iain,Dayal, Satish,Pike, Andrew,Webster, Rob,Pryde, David C.
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p. 1387 - 1396
(2014/07/21)
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- DIPEPTIDE AND TRIPEPTIDE EPOXY KETONE PROTEASE INHIBITORS
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Provided herein are dipeptide and tripeptide epoxy ketone protease inhibitors, methods of their preparation, related pharmaceutical compositions, and methods of using the same. For example, provided herein are compounds of Formula (X): and pharmaceutically acceptable salts and compositions including the same. The compounds and compositions provided herein may be used, for example, in the treatment of proliferative diseases including cancer and autoimmune diseases.
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Paragraph 00198; 00199
(2014/10/04)
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- HETEROARYL BTK INHIBITORS
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The present invention provides compounds useful as inhibitors of Btk, compositions thereof, and methods of using the same.
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Page/Page column 121
(2011/04/14)
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