- Phenyl 1, 2 - isoxazole or phenyl 1, 2 - pyrazole compound and use thereof (by machine translation)
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The invention discloses the following formula of phenyl 1, 2 - different oxazole or 1, 2 - pyrazole compounds with use. Through the biological activity tests show that, the compound inhibiting heat shock protein 90 activity. Therefore, the invention phenyl 1, 2 - different oxazole or 1, 2 - pyrazole compounds can be used as a heat shock protein 90 inhibitor for the treatment of cancer. (by machine translation)
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Paragraph 0435; 0436; 0438; 0439; 0440; 0441
(2017/01/19)
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- 4,5-Diarylisoxazole Hsp90 chaperone inhibitors: Potential therapeutic agents for the treatment of cancer
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Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure - activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by ~50%.
- Brough, Paul A.,Aherne, Wynne,Barril, Xavier,Borgognoni, Jenifer,Boxall, Kathy,Cansfield, Julie E.,Cheung, Kwai-Ming J.,Collins, Ian,Davies, Nicholas G. M.,Drysdale, Martin J.,Dymock, Brian,Eccles, Suzanne A.,Finch, Harry,Fink, Alexandra,Hayes, Angela,Howes, Robert,Hubbard, Roderick E.,James, Karen,Jordan, Allan M.,Lockie, Andrea,Martins, Vanessa,Massey, Andrew,Matthews, Thomas P.,McDonald, Edward,Northfield, Christopher J.,Pearl, Laurence H.,Prodromou, Chrisostomos,Ray, Stuart,Raynaud, Florence I.,Roughley, Stephen D.,Sharp, Swee Y.,Surgenor, Allan,Walmsley, D. Lee,Webb, Paul,Wood, Mike,Workman, Paul,Wright, Lisa
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p. 196 - 218
(2008/09/17)
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- ISOXAZOLE COMPOUNDS AS INHIBITORS OF HEAT SHOCK PROTEINS
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Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: (A), (B) wherein R1, is a group of formula (IA): -Ar1-(Alk1)p-(Z)r-(Alk2)S-Q, wherein in any compatible combination Ar1 is an optionally substituted aryl or heteroaryl radical, Alk1and Alk2 are optionally substituted divalent Cl-C6 alkylene or C2-C6 alkenylene radicals, p, r and s are independently 0 or 1, Z is -0-, -S-, -(C=O)-, -(C=S)-, -SO2-, -C(=O)O-, -C(=O)NRA-, -C(=S)NRA-, - SO2NRA-, -NRAC(=O)-, -NRASO2- or -NRA- wherein RA is hydrogen or Cl-C6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R2 is (i) a group of formula (IA) above or (ii) a carboxamide radical; or (iii) a non aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula -(Alk1)p-(Z)r-(Alk2)s-Q wherein Q, Alk1, Alk2, Z, p, r and s are as defined above in relation to group (IA); and R3 is hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl; or a carboxyl, carboxamide, or carboxyl ester group.
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- Anti-AIDS agents. 60. Substituted 3′R,4′R-di-O-(-)-camphanoyl- 2′,2′-dimethyldihydropyrano[2,3-f]chromone (DCP) analogues as potent anti-HIV agents
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Synthesis of positional isomers is a commonly used technique in drug design. Accordingly, based on prior SAR studies of 3′R,4′R-di-O-(S)- camphanoyl-(+)-cis-khellactone (DCK, 1) analogues, a series of mono- and disubstituted chromone derivatives of 3′R,4′R-di-O-(-)camphanoyl- 2′,2′-dimethyldihydropyrano[2,3-f]chromone (DCP, 4) were designed and synthesized. Together with 1 and 4-methyl DCK (2), all newly synthesized DCP analogues (4-21) were screened for anti-HIV-1 activity against a non-drug-resistant strain in H9 lymphocytes and a multiple reverse transcriptase (RT) inhibitor-resistant strain in the MT4 cell line. Several DCP analogues (4, 5, 7, 8, 13, and 17) exhibited extremely high anti-HIV activity in the nondrug-resistant strain assay, with EC50 values ranging from 0.00032 to 0.0057 μM and remarkable therapeutic indexes (TI) ranging from 5.6 × 103 to 1.16 × 105, which were similar to those of 2 (EC50 0.0059 μM, TI > 6.6 × 103) and better than those of 1 (EC50 0.049 μM, TI > 328). Even more promisingly, some DCP analogues also showed activity against a multi-RT inhibitor-resistant strain, HIV-1 RTMDR1, whereas most DCK analogues did not. The most significant compound was 8, with an EC50 value of 0.06 μM and TI of 718 against the multi-RT inhibitor-resistant HIV-1 strain. Compounds 9 and 10 also showed good activity with an EC50 value of 0.14 μM, and TIs of 272 and >111, respectively. 2-Ethyl DCP (8) exhibited the best anti-HIV activity in both assays. Further development of 8-related compounds as clinical trial candidates is warranted.
- Yu, Donglei,Chen, Chin-Ho,Brossi, Arnold,Lee, Kuo-Hsiung
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p. 4072 - 4082
(2007/10/03)
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- Leukotriene B4 Receptor Antagonists: The LY255283 Series of Hydroxyacetophenones
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A series of hydroxyacetophenones was prepared for evaluation as leukotriene B4 (LTB4) receptor antagonists, culminating in 1-oxy>phenyl>ethanone (compound 35, LY255283).Using an assay for inhibition of specific LTB4 binding to human PMN, we found that substitution of a nonpolar substituent in the 5-position was required for activity.Best activity was realized with hydrogen in the 3-position, hydroxyl in the 2-position, short chain alkyl ketone in the 1-position, and a six- or eight-carbon chain linking the oxygen in the 4-position with an unsaturated terminal function.Compound 35, having an IC50 of 87 nM in the binding assay, was chosen for further preclinical evaluation.
- Herron, David K.,Goodson, Theodore,Bollinger, Nancy G.,Swanson-Bean, Dorothy,Wright, Ian G.,et al.
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p. 1818 - 1828
(2007/10/02)
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