- Optimization of a Benzoylpiperidine Class Identifies a Highly Potent and Selective Reversible Monoacylglycerol Lipase (MAGL) Inhibitor
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Monoacylglycerol lipase (MAGL) is the enzyme degrading the endocannabinoid 2-arachidonoylglycerol, and it is involved in several physiological and pathological processes. The therapeutic potential of MAGL is linked to several diseases, including cancer. The development of MAGL inhibitors has been greatly limited by the side effects associated with the prolonged MAGL inactivation. Importantly, it could be preferable to use reversible MAGL inhibitors in vivo, but nowadays only few reversible compounds have been developed. In the present study, structural optimization of a previously developed class of MAGL inhibitors led to the identification of compound 23, which proved to be a very potent reversible MAGL inhibitor (IC50 = 80 nM), selective for MAGL over the other main components of the endocannabinoid system, endowed of a promising antiproliferative activity in a series of cancer cell lines and able to block MAGL both in cell-based as well as in vivo assays.
- Granchi, Carlotta,Lapillo, Margherita,Glasmacher, Sandra,Bononi, Giulia,Licari, Cristina,Poli, Giulio,El Boustani, Maguie,Caligiuri, Isabella,Rizzolio, Flavio,Gertsch, Jürg,Macchia, Marco,Minutolo, Filippo,Tuccinardi, Tiziano,Chicca, Andrea
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p. 1932 - 1958
(2019/02/26)
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- A α, α-diphenyl-4-piperidine methanol synthesis method
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The invention discloses a method for synthesis of alpha,alpha-diphenyl-4-piperidine methanol. The method comprises the steps: taking 4-piperidine formic acid as a raw material, carrying out a reaction with an acetylation reagent to obtain N-acetyl piperidine formic acid; firstly generating N-acetyl piperidine formyl chloride from the obtained N-acetyl piperidine formic acid, and then carrying out a Friedel-Crafts acylation reaction with benzene to generate N-acetyl-4-benzoyl piperidine; carrying out a Grignard reaction of the obtained N-acetyl-4-benzoyl piperidine with phenyl magnesium halide to obtain N-acetyl-alpha,alpha-diphenyl-4-piperidine methanol; and deacetylating the N-acetyl-alpha,alpha-diphenyl-4-piperidine methanol to obtain the alpha,alpha-diphenyl-4-piperidine methanol. The synthesis method has the characteristics of cheap and easily obtained raw materials, simple process steps, high reaction yield and low costs of raw materials, and is suitable for industrialized production.
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Paragraph 0035; 0038; 0039
(2017/04/04)
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- PIPERIDINE UREA DERIVATIVES
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Compounds of the formula I in which R1-R3 have the meanings indicated in Claim 1, are inhibitors of Tankyrase, and can be employed, inter alia, for the treatment of diseases such as cancer, cardiovascular diseases, central nervous system injury and different forms of inflammation.
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Page/Page column 42
(2015/02/25)
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- Discovery of the disubstituted oxazole analogues as a novel class anti-tuberculotic agents against MDR- and XDR-MTB
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A high-throughput screening effort on 45,000 compounds resulted in the discovery of a disubstituted oxazole as a new structural class inhibitor of Mycobacterium tuberculosis (Mtb). In order to improve the activity and investigate the SAR of this scaffold, a series of disubstituted azole analogues have been designed and synthesized. The newly synthesized compounds 1a-y were evaluated for their in vitro anti-TB activity versus replicating, multi- and extensive drug resistant Mtb strains. All the compounds, except 1o, 1p and 1q, showed potent anti-TB activity with MIC of 1-64 mg/L. The test of broad spectrum panel revealed that this series are specific to Mtb. The cytotoxicity assessment indicated that the compounds were not cytotoxic against HEK 293 cells. The compounds could have a novel mechanism to anti-Mtb as they can inhibit drug sensitive and drug resistant Mtb.
- Li, Dongsheng,Gao, Nana,Zhu, Ningyu,Lin, Yuan,Li, Yan,Chen, Minghua,You, Xuefu,Lu, Yu,Wan, Kanglin,Jiang, Jian-Dong,Jiang, Wei,Si, Shuyi
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supporting information
p. 5178 - 5181
(2015/11/09)
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- PHENYL LINKED QUINOLINYL MODULATORS OF RORyt
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The present invention comprises compounds of Formula I. wherein: R1, R2, R3, R4, R5, R6, R7, R8, and R9 are defined in the specification. The invention also
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Paragraph 0203
(2015/04/21)
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- METHYLENE LINKED QUINOLINYL MODULATORS OF RORyt
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The present invention comprises compounds of Formula I. wherein: R1, R2, R3, R4, R5, R6, R7, R8, and R9 are defined in the specification. The invention also comprises a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is rheumatoid arthritis or psoriasis. The invention also comprises a method of modulating RORγt activity in a mammal by administration of a therapeutically effective amount of at least one compound of claim 1.
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Paragraph 0294; 0295
(2015/04/21)
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- METHYLENE LINKED QUINOLINYL MODULATORS OF ROR-GAMMA-T
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The present invention comprises compounds of Formula (I). wherein: R1, R2, R3, R4, R5, R6, R7, R8, and R9 are defined in the specification. The invention also comprises a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is rheumatoid arthritis or psoriasis. The invention also comprises a method of modulating RORγt activity in a mammal by administration of a therapeutically effective amount of at least one compound of claim 1.
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Page/Page column 86; 87
(2015/05/05)
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- QUINOLINYL MODULATORS OF RORyt
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The present invention comprises compounds of Formula I. wherein: R1, R2, R3, R4, R5, R6, R7, R8, and R9 are defined in the specification. The invention also comprises a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is rheumatoid arthritis or psoriasis. The invention also comprises a method of modulating RORγt activity in a mammal by administration of a therapeutically effective amount of at least one compound of claim 1.
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Paragraph 0353; 0354
(2015/04/28)
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- METHYLENE LINKED QUINOLINYL MODULATORS OF RORyt
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The present invention comprises compounds of Formula I. wherein: R1, R2, R3, R4, R5, R6, R7, R8, and R9 are defined in the specification. The invention also comprises a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is rheumatoid arthritis or psoriasis. The invention also comprises a method of modulating RORγt activity in a mammal by administration of a therapeutically effective amount of at least one compound of claim 1.
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Paragraph 0635; 0636
(2014/05/07)
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- HETEROARYL LINKED QUINOLINYL MODULATORS OF RORyt
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The present invention comprises compounds of Formula I. wherein: R1, R2, R3, R4, R5, R6, R7, R8, and R9 are defined in the specification. The invention also comprises a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is rheumatoid arthritis or psoriasis. The invention also comprises a method of modulating RORγt activity in a mammal by administration of a therapeutically effective amount of at least one compound of claim 1.
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Paragraph 0340; 0341
(2014/05/07)
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- Syntheses and Binding Studies of New [(Aryl)(aryloxy)methyl]piperidine Derivatives and Related Compounds as Potential Antidepressant Drugs with High Affinity for Serotonin (5-HT) and Norepinephrine (NE) Transporters
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In a wide search program toward new, efficient, and fast-acting antidepressant drugs, we have prepared series of new compounds having an (aryl)(aryloxy)methyl moiety linked directly or through a methylene chain to different substituted and unsubstituted cycles (isoquinoline, piperazine, piperidine, tetrahydropyran, or cyclopentane). These compounds have been evaluated for their affinities for serotonin (5-HT) transporter (SERT) and 5-HT1A and 5-HT2A receptors. Racemic mixtures of 4-[(aryl)(aryloxy)methyl]piperidine derivatives showed much higher affinity values for SERT than fluoxetine and resulted in lack of affinity for 5-HT 1A and 5-HT2A receptors. Some of these racemic mixtures were resolved to their enantiomers and tested for binding to norepinephrine (NE) transporter (NET), dopamine (DA) transporter (DAT), and α2 receptor. Several of these enantiomers [(-)-15b, (-)-15j, (-)-15t, (+)-15u] displayed a dual binding profile with affinities for SERT and NET with K i i = 1.9 and 13.5 nM, respectively), and further pharmacological characterization is in progress for its evaluation as a antidepressant.
- Orjales, Aurelio,Mosquera, Ramón,Toledo, Antonio,Pumar, M. Carmen,García, Neftalí,Cortizo, Lourdes,Labeaga, Luis,Innerárity, Ana
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p. 5512 - 5532
(2007/10/03)
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