- Lanosterol 14α-demethylase (CYP51)/histone deacetylase (HDAC) dual inhibitors for treatment of Candida tropicalis and Cryptococcus neoformans infections
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Invasive fungal infections remain a challenge due to lack of effective antifungal agents and serious drug resistance. Discovery of antifungal agents with novel antifungal mechanism is important and urgent. Previously, we designed the first CYP51/HDAC dual
- Zhu, Tianbao,Chen, Xi,Li, Chenglan,Tu, Jie,Liu, Na,Xu, Defeng,Sheng, Chunquan
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- Exploiting the tolerant region I of the non-nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket. Part 2: Discovery of diarylpyrimidine derivatives as potent HIV-1 NNRTIs with high Fsp3 values and favorable drug-like properties
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To yield potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with favorable drug-like properties, a series of novel diarylpyrimidine derivatives targeting the tolerant region I of the NNRTI binding pocket were designed, synthesized and b
- Jiang, Xiangyi,Huang, Boshi,Olotu, Fisayo A.,Li, Jing,Kang, Dongwei,Wang, Zhao,De Clercq, Erik,Soliman, Mahmoud E.S.,Pannecouque, Christophe,Liu, Xinyong,Zhan, Peng
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- Identification of novel potent HIV-1 inhibitors by exploiting the tolerant regions of the NNRTIs binding pocket
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With our previously identified potent NNRTIs 25a and HBS-11c as leads, series of novel thiophene[3,2-d]pyrimidine and thiophene[2,3-d]pyrimidine derivatives were designed via molecular hybridization strategy. All the target compounds were evaluated for their anti-HIV-1 activity and cytotoxicity in MT-4 cells. Compounds 16a1 and 16b1 turned out to be the most potent inhibitors against WT and mutant HIV-1 strains (L100I, K103N, and E138K), with EC50 values ranging from 0.007 μM to 0.043 μM. Gratifyingly, 16b1 exhibited significantly reduced cytotoxicity (CC50 > 217.5 μM) and improved water solubility (S = 49.3 μg/mL at pH 7.0) compared to the lead 25a (S 50 = 2.30 μM). Moreover, molecular docking was also conducted to rationalize the structure-activity relationships of these novel derivatives and to understand their key interactions with the binding pocket.
- Sun, Yanying,Kang, Dongwei,Da, Feng,Zhang, Tao,Li, Pei,Zhang, Baodan,De Clercq, Erik,Pannecouque, Christophe,Zhan, Peng,Liu, Xinyong
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- Triazole CYP51-HDAC double-target antifungal compound as well as preparation method and application thereof
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The invention discloses a triazole CYP51-HDAC double-target antifungal compound, which has a structural general formula disclosed in the invention, wherein R is selected from one of the structures disclosed in the invention. According to the triazole CYP5
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- Exploiting the Tolerant Region i of the Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Binding Pocket: Discovery of Potent Diarylpyrimidine-Typed HIV-1 NNRTIs against Wild-Type and E138K Mutant Virus with Significantly Improved Water Solubility an
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Diarylpyrimidine derivatives (DAPYs) exhibit robust anti-HIV-1 potency, although they have been compromised by E138K variant and severe side-effects and been suffering from poor water solubility. In the present work, hydrophilic morpholine or methylsulfon
- Huang, Boshi,Chen, Wenmin,Zhao, Tong,Li, Zhenyu,Jiang, Xiangyi,Ginex, Tiziana,Vílchez, David,Luque, Francisco Javier,Kang, Dongwei,Gao, Ping,Zhang, Jian,Tian, Ye,Daelemans, Dirk,De Clercq, Erik,Pannecouque, Christophe,Zhan, Peng,Liu, Xinyong
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p. 2083 - 2098
(2019/03/07)
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- Discovery of 4-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazole-3-carboxamide (FN-1501), an FLT3- and CDK-Kinase Inhibitor with Potentially High Efficiency against Acute Myelocytic Leukemia
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A series of 1-H-pyrazole-3-carboxamide derivatives have been designed and synthesized that exhibit excellent FLT3 and CDK inhibition and antiproliferative activities. A structure-activity-relationship study illustrates that the incorporation of a pyrimidine-fused heterocycle at position 4 of the pyrazole is critical for FLT3 and CDK inhibition. Compound 50 (FN-1501), which possesses potent inhibitory activities against FLT3, CDK2, CDK4, and CDK6 with IC50 values in the nanomolar range, shows antiproliferative activities against MV4-11 cells (IC50: 0.008 μM), which correlates with the suppression of retinoblastoma phosphorylation, FLT3, ERK, AKT, and STAT5 and the onset of apoptosis. Acute-toxicity studies in mice show that compound 50 (LD50: 186 mg/kg) is safer than AT7519 (32 mg/kg). In MV4-11 xenografts in a nude-mouse model, compound 50 can induce tumor regression at the dose of 15 mg/kg, which is more efficient than cytarabine (50 mg/kg). Taken together, these results demonstrate the potential of this unique compound for further development into a drug applied in acute-myeloid-leukemia (AML) therapeutics.
- Wang, Yue,Zhi, Yanle,Jin, Qiaomei,Lu, Shuai,Lin, Guowu,Yuan, Haoliang,Yang, Taotao,Wang, Zhanwei,Yao, Chao,Ling, Jun,Guo, Hao,Li, Tonghui,Jin, Jianlin,Li, Baoquan,Zhang, Li,Chen, Yadong,Lu, Tao
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p. 1499 - 1518
(2018/03/05)
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- 1,3,4-OXADIAZOLE SULFONAMIDE DERIVATIVE COMPOUNDS AS HISTONE DEACETYLASE 6 INHIBITOR, AND THE PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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The present invention relates to novel compounds represented by the formula I having histone deacetylase 6 (HDAC6) inhibitory activity, stereoisomers thereof or pharmaceutically acceptable salts thereof, the use thereof for the preparation of therapeutic medicaments, pharmaceutical compositions containing the same, a method for treating diseases using the composition, and methods for preparing the novel compounds. (I) The novel compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof according to the present invention have histone deacetylase (HDAC) inhibitory activity and are effective for the prevention or treatment of HDAC6-mediated diseases.
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- NEW FYN KINASE INHIBITORS
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The invention relates to new selective FYN kinase inhibitors of Formula (I), pharmaceutical compositions containing them, and their use for the pharmacological treatment of pain and arthritis, including osteoarthritis and rheumatoid arthritis.
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- FAK AND FLT3 INHIBITORS
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The use of a compound of the formula (I): (Formula (I)) in the preparation of a medicament for treating Acute Myeloid Leukemia or a disease ameliorated by the inhibition of Flt3, or Flt3 and FAK.
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- FAK INHIBITORS
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A compound of the formula (I): where R1 or R2 is a cycle amine group and R5 is an aromatic group with a carbonyl containing substituent for use as a FAK inhibitor.
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- PIPERAZINYL DERIVATIVES USEFUL IN THE TREATMENT OF GPR38 RECEPTOR MEDIATED DISEASES
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The invention relates to compounds of formula (I), processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of conditions or disorders which are mediated via the GPR38 receptor.
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Page/Page column 45
(2008/06/13)
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- BENZYLPIPERAZINE DERIVATIVES AS MOTILIN RECEPTOR ANTAGONISTS
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The invention relates to compounds of formula (I) processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of conditions or disorders which are mediated via the GPR38 receptor.
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Page/Page column 40-41
(2008/06/13)
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- INHIBITORS OF C-FMS KINASE
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The invention is directed to compounds of Formula I: wherein Z, X, J, R2 and W are set forth in the specification, as well as solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase. Methods of treating autoimmune diseases; and diseases with an inflammatory component; treating metastasis from ovarian cancer, uterine cancer, breast cancer, colon cancer, stomach cancer, hairy cell leukemia and non-small lung carcinoma; and treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; as well as osteoporosis, Paget's disease, and other diseases in which bone resorption mediates morbidity including arthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone with the compounds of Formula I, are also provided.
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Page/Page column 116
(2008/06/13)
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- Phenoxypiperidines and analogs thereof useful as histamine H3 antagonists
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Disclosed are compounds of the formula or a pharmaceutically acceptable salt or solvate thereof, wherein: M is CH or N; U and W are each CH, or one of U and W is CH and the other is N; X is a bond, alkylene, —C(O)—, —C(N—OR5)—, —C(N—OR5)—CH(R6)—, —CH(R6)—C(N—OR5)—, —O—, —OCH2—, —CH2O— or —S(O)0-2—; Y is —O—, —(CH2)2—, —C(═O)—, —C(═NOR7)— or —SO0-2—; Z is a bond, optionally substituted alkylene or alkylene interrupted by a heteroatom or heterocyclic group; R1 is optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocycloalkyl, or benzimidazolyl or a derivative thereof; R2 is optionally substituted alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; and the remaining variables are as defined in the specification; compositions and methods for treating an allergy-induced airway response, congestion, diabetes, obesity, an obesity-related disorder, metabolic syndrome and a cognition deficit disorder using said compounds, alone or in combination with other agents.
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Page/Page column 47
(2010/11/27)
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- Synthesis and evaluation of a DHA and 10-hydroxycamptothecin conjugate
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We have synthesized a conjugate of cis-4,7,10,13,16,19-docosahexenoic acid (DHA) and 10-hydroxycamptothecin (HCPT), DHA-HCPT. The antitumor activity of DHA-HCPT was evaluated in vitro against L1210 leukemia cells and in experimental animal tumor models in
- Wang, Yuqiang,Li, Lianfa,Jiang, Wei,Larrick, James W.
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p. 5592 - 5599
(2007/10/03)
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- Substituted indolines which inhibit receptor tyrosine kinases
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Indolinones of the formula having an inhibitory effect on receptor tyrosine kinases and cyclin/CDK complexes, as well as on the proliferation of endothelial cells and various tumor cells. Exemplary are: (a) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone, (b) 3-Z-[(1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone, and (c) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-metboxycarbonyl-2-indolinone.
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Page column 47
(2008/06/13)
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- Novel anticancer conjugates of camptothecin and unsaturated fatty acids
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The present invention provides novel conjugates of camptothecin compounds and long-chain unsaturated fatty acid. The novel conjugates can be used to treat mammalian cell proliferative diseases such as cancer.
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Page/Page column 12; Sheet 1
(2008/06/13)
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- Substituted indolinones, preparation thereof and their use as pharmaceutical compositions
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Indolinones of general formula I which are inhibitors of cell proliferation, particularly of tumour cells, and inhibitors of protein kinases. The following compounds are exemplary: (Z)-3-{1-[4-(N-(2-aminoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone, (Z)-3-{1 -[4-(N-(2-dimethylaminoethyl)-N-phenylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone, and (Z)-3-{1-[4-(4-methylpiperazinomethyl)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone.
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- Substituted indolinones with kinase inhibitory activity
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Substituted indolinones of general formula having effect on various kinases and cycline/CDK complexes and on the proliferation of various tumour cells. Exemplary compounds are: 3-Z-[1-(4-(N-Benzyl-N-methyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-a
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- A novel series of 2-carboxytetrahydroquinolines provides new insights into the eastern region of glycine site NMDA antagonists
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A series of potent 4-substituted tetrahydroquinolines has been synthesized and biologically tested in order to refine the eastern region of the pharmacophore model for glycine site NMDA antagonists concerning the assessment of lipophilicity, flexibility, and hydrogen bonding. Displacement studies on rat cortical membranes using [3H]-5,7-dichlorokynurenic acid as a radioligand indicated that binding affinities are markedly enhanced when additional hydrogen-accepting groups are introduced into the eastern region of the 2-carboxytetrahydroquinolines. Among the most potent ligands were some urea, sulfonylurea, and crown ether compounds as interesting leads for new diagnostics, especially for the evaluation of PET tracers, which allow biodistribution studies and NMDA receptor studies in the living organism.
- Dannhardt, Gerd,Gruchalla, Markus V.,Kohl, Beate K.,Parsons
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p. 267 - 274
(2007/10/03)
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