- Design, synthesis and stepwise optimization of nitrile-based inhibitors of cathepsins B and L
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Human cathepsin B (CatB) is an important biological target in cancer therapy. In this work, we performed a knowledge-based design approach and the synthesis of a new set of 19 peptide-like nitrile-based cathepsin inhibitors. Reported compounds were assayed against a panel of human cysteine proteases: CatB, CatL, CatK, and CatS. Three compounds (7h, 7i, and 7j) displayed nanomolar inhibition of CatB and selectivity over CatK and CatL. The selectivity was achieved by using the combination of a para biphenyl ring at P3, halogenated phenylalanine in P2 and Thr-O-Bz group at P1. Likewise, compounds 7i and 7j showed selective CatB inhibition among the panel of enzymes studied. We have also described a successful example of bioisosteric replacement of the amide bond for a sulfonamide one [7e → 6b], where we observed an increase in affinity and selectivity for CatB while lowering the compound lipophilicity (ilogP). Our knowledge-based design approach and the respective structure–activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cathepsins.
- Cianni, Lorenzo,Rocho, Fernanda Dos Reis,Bonatto, Vinícius,Martins, Felipe Cardoso Prado,Lameira, Jer?nimo,Leit?o, Andrei,Montanari, Carlos A.,Shamim, Anwar
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- Structure-based drug optimization and biological evaluation of tetrahydroquinolin derivatives as selective and potent CBP bromodomain inhibitors
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CBP bromodomain could recognize acetylated lysine and function as transcription coactivator to regulate transcription and downstream gene expression. Furthermore, CBP has been shown to be related to many human malignancies including acute myeloid leukemia. Herein, we identified DC-CPin734 as a potent CBP bromodomain inhibitor with a TR-FRET IC50 value of 19.5 ± 1.1 nM and over 400-fold of selectivity against BRD4 bromodomains through structure based rational drug design guided iterative chemical modification endeavoring to discover optimal tail-substituted tetrahydroquinolin derivatives. Moreover, DC-CPin734 showed potent inhibitory activity to AML cell line MV4-11 with an IC50 value of 0.55 ± 0.04 μM, and its cellular on-target effects were further evidenced by c-Myc downregulation results. In summary, DC-CPin734 showing good potency, selectivity and anti AML activity could serve as a potent and selective in vitro and in vivo probe of CBP bromodomain and a promising lead compound for future drug development.
- Bi, Xiaoyang,Chen, Yu,Sun, Zhongya,Lu, Wenchao,Xu, Pan,Lu, Tian,Ding, Hong,Zhang, Naixia,Jiang, Hualiang,Chen, Kaixian,Zhou, Bing,Luo, Cheng
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supporting information
(2020/09/16)
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- Cadmium-based metal organic framework material as well as preparation method and application thereof
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The invention discloses a cadmium-based metal organic framework material as well as a preparation method and an application thereof. The preparation method of the cadmium-based metal organic frameworkmaterial comprises steps as follows: 1) synthesis of li
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Paragraph 0041-0043; 0056-0058; 0061-0063
(2020/03/29)
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- Synthesis and biological evaluation of novel aromatic-heterocyclic biphenyls as potent anti-leukemia agents
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As a continuation to our previous research, twenty-eight aromatic-heterocyclic biphenyls were designed and synthesized as novel Bcr-Abl inhibitors. The title compounds were investigated for their antiproliferative activities against wild K562 cells and Imatinib-resistant K562 cells (K562R). The results indicated that most of them exhibited potent Bcr-Abl inhibition and moderate antiproliferative potency against K562 cells. Furthermore, three compounds 3, 7 and 21 displayed moderate antiproliferative activities against K562R cells. Molecular docking indicated that 3 bound more tightly with Bcr-AblT315I compared to Bcr-AblWT. The higher affinity was consistent with its relatively promising K562R cell growth inhibition. These aromatic-heterocyclic biphenyls could be considered as novel lead compound for optimized as Bcr-AblT315I inhibitors. They provide a good starting point for the further development of novel anti-leukemia agents capable of dealing with clinical acquired resistance against Imatinib.
- Dong, Jinyun,Pan, Xiaoyan,Wang, Jinfeng,Su, Ping,Zhang, Lin,Wei, Fen,Zhang, Jie
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p. 780 - 789
(2015/08/06)
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- PYRROLIDINE OR THIAZOLIDINE CARBOXYLIC ACID DERIVATIVES, PHARMACEUTICAL COMPOSITION AND METHODS FOR USE IN TREATING METABOLIC DISORDERSAS AS AGONISTS OF G- PROTEIN COUPLED RECEPTOR 43 (GPR43)
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The present invention is directed to novel compounds of formula (I) and their use in treating and/or preventing metabolic diseases.
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Page/Page column 202
(2011/07/07)
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- HISTAMINE H3 RECEPTOR AGENTS, PREPARATION AND THERAPEUTIC USES
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The present invention discloses novel compounds of Formula (I) or pharmaceutically acceptable salts thereof, which have histamine-H3 receptor antagonist or inverse agonist activity, as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising compounds of Formula (I) as well as methods of using them to treat obesity, cognitive deficiencies, narcolepsy, and other histamine H3 receptor-related diseases
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Page/Page column 14; 15
(2010/03/31)
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- BENZOXAZOLE CARBOXAMIDE INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE (PARP)
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A compound having the structure set forth in Formula (I) or Formula (II): wherein the variables Y, R1, R2, R3, and R4 are as defined herein. Provided herein are inhibitors of poly(ADP-ribose)polymerase activity. Also described herein are pharmaceutical compositions that include at least one compound described herein and the use of a compound or pharmaceutical composition described herein to treat diseases, disorders and conditions that are ameliorated by the inhibition of PARP activity.
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Page/Page column 73-74
(2009/08/16)
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- Structural modifications of salicylates: Inhibitors of human CD81-receptor HCV-E2 interaction
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Starting point of the present paper was the result of a virtual screening using the open conformation of the large extracellular loop (LEL) of the CD81-receptor (crystal structure: PDB-ID: 1G8Q). After benzyl salicylate had been experimentally validated to be a moderate inhibitor of the CD81-LEL-HCV-E2 interaction, further optimization was performed and heterocyclic-substituted benzyl salicylate derivatives were synthesized. The compounds were tested for their ability to inhibit the interaction of a fluorescence-labeled antibody to CD81-LEL using HUH7.5 cells. No compound showed an increase concerning the inhibition of the protein-protein interaction compared to benzyl salicylate.
- Holzer, Marcel,Ziegler, Sigrid,Neugebauer, Alexander,Kronenberger, Bernd,Klein, Christian D.,Hartmann, Rolf W.
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experimental part
p. 478 - 484
(2009/04/04)
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- HISTAMINE H3 RECEPTOR AGENTS, PREPARATION AND THERAPEUTIC USES
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The present invention discloses novel compounds of Formula (I) or pharmaceutically acceptable salts thereof, which have histamine-H3 receptor antagonist or inverse agonist activity, as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising compounds of Formula (I) as well as methods of using them to treat obesity, cognitive deficiencies, narcolepsy, and other histamine H3 receptor-related diseases
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Page/Page column 37
(2008/06/13)
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- Biarylcarboxybenzamide derivatives as potent vanilloid receptor (VR1) antagonistic ligands
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Seventeen biarylcarboxybenzamide derivatives were prepared for the study of their agonistic/antagonistic activities to the vanilloid receptor (VR1) in rat DRG neurons. The replacement of the piperazine moiety of the lead compound 1 with phenyl ring showed quite enhanced antagonistic activity. Among the prepared derivatives, N-(4-tert-butylphenyl)-4-pyridine-2-yl-benzamide (2, IC 50 = 31 nM) and N-(4-tert-butylphenyl)-4-(3-methylpyridine-2-yl) benzamide (3g, IC50 = 31 nM), showed 5-fold higher antagonistic activity than 1 in 45Ca2+-influx assay.
- Park, Hyeung-Geun,Choi, Ji-Yeon,Kim, Mi-Hyun,Choi, Sea-Hoon,Park, Mi-Kyung,Lee, Jihye,Suh, Young-Ger,Cho, Hawon,Oh, Uhtaek,Kim, Hee-Doo,Joo, Yung Hyup,Shin, Song Seok,Kim, Jin Kwan,Jeong, Yeon Su,Koh, Hyun-Ju,Park, Young-Ho,Jew, Sang-Sup
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p. 631 - 634
(2007/10/03)
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- PIPERIDINES USEFUL FOR THE TREATMENT OF CENTRAL NERVOUS SYSTEM DISORDERS
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The invention relates to compounds which are substituted chiral or achiral derivatives of 3- or 4- aminopiperidine of the general formula (I). The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of general formula I and especially their use as inhibitors of β-secretases.
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- SUBSTITUTED (AMINOIMINOMETHYL OR AMINOMETHYL) BENZOHETEROARYL COMPOUNDS
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This invention is directed to an (aminoiminomethyl or aminomethyl) benzoheteroaryl compound of formula I which is useful for inhibiting the activity of Factor Xa by combining said compound with a composition containing Factor Xa. The present invention is also directed to compositions containing compounds of the formula I, methods for their preparation, their use, such as in inhibiting the formation of thrombin or for treating a patient suffering from, or subject to, a disease state associated with a physiologically detrimental excess amount of thrombin.
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- Substituted (aminoiminomethyl or aminomethyl) dihydrobenzofurans and benzopyrans
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This invention is directed to substituted (aminoiminomethyl or aminomethyl) dihydrobenzofurans and benzopyrans that inhibit Factor Xa, pharmaceutical compositions comprising these compounds and their use for inhibiting Factor Xa or treating pathological conditions in a patient that may be ameliorated by administration of such compounds. This invention is also is also directed to substituted (aminoiminomethyl or aminomethyl) dihydrobenzofurans and benzopyrans which directly inhibit both Factor Xa and Factor IIa (thrombin), to pharmaceutical compositions comprising these compounds, to intermediates useful for preparing these compounds and to a method of simultaneously directly inhibiting both Factor Xa and Factor IIa (thrombin).
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- Sulfonamide derivatives, their production and use
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The present invention provides compounds which specifically inhibit FXa, which are effective when orally administered and which are useful as a safe medicine for the prevention or treatment of diseases caused by thrombus or infarction. Compounds of this invention are piperazinones of the formula: wherein R1is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; the ring A is an optionally substituted divalent nitrogen-containing heterocyclic group, in addition to being substituted by the group of the formula: and the group of the formula: Y is an optionally substituted divalent hydrocarbon group or an optionally substituted divalent heterocyclic group; X is a direct bond or an optionally substituted alkylene chain; Z is (1) an amino group substituted with an optionally substituted hydrocarbon group, (2) an optionally substituted imino group or (3) an optionally substituted nitrogen-containing heterocyclic group; provided that when X is a direct bond and Z is an optionally substituted 6-membered nitrogen-containing aromatic heterocyclic group, Y is an optionally substituted divalent hydrocarbon group or an optionally substituted divalent unsaturated heterocyclic group; or a salt thereof.
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Referential example 13
(2010/11/29)
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- COMPOUNDS AND METHODS
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This invention relates to substituted heteroanilide compounds which are modulators, agonists or antagonists, of the CCR5 receptior. In addition, this invention relates to the treatment and prevention of disease states mediatd by CCR5.
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- A convenient synthesis of heteroaryl benzoic acids via Suzuki reaction
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An one step approach to heteroaryl benzoic acids from readily accessible heteroaryl halides and carboxybenzene boronic acids is described. The Suzuki coupling is carried out in the presence of Pd(PPh3)4 and sodium carbonate in aqueous acetonitrile. The scope and limitations of the reaction are discussed.
- Gong, Yong,Pauls, Henry W.
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p. 829 - 831
(2007/10/03)
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