49783-72-4Relevant academic research and scientific papers
Toxoflavins and deazaflavins as the first reported selective small molecule inhibitors of tyrosyl-DNA phosphodiesterase II
Raoof, Ali,Depledge, Paul,Hamilton, Niall M.,Hamilton, Nicola S.,Hitchin, James R.,Hopkins, Gemma V.,Jordan, Allan M.,Maguire, Laura A.,McGonagle, Alison E.,Mould, Daniel P.,Rushbrooke, Mathew,Small, Helen F.,Smith, Kate M.,Thomson, Graeme J.,Turlais, Fabrice,Waddell, Ian D.,Waszkowycz, Bohdan,Watson, Amanda J.,Ogilvie, Donald J.
, p. 6352 - 6370 (2013/09/23)
The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAR) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge.
Pyrazolo[3,4-b]pyridine compounds, and their use as a PDE4 inhibitors
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Page/Page column 128-129, (2009/05/28)
The invention provides a compound of formula (I) or a salt thereof: wherein R2 is H, C1-3alkyl, n-butyl, C1-2fluoroalkyl, cyclopropyl, cyclobutyl, (cyclopropyl)methyl-, —CN, or —CH2OH; R3 is inter alia optionally substituted C4-7cycloalkyl or an optionally substituted heterocyclic group (aa), (bb) or (cc); Ra is H, methyl or ethyl; Rb is H or methyl; R4 is H, methyl, ethyl, n-propyl, —C(O)-Me, or —C(O)—C1fluoroalkyl; and R5 is: —C(O)—(CH2)n—Ar, —C(O)-Het, —C(O)—C1-6alkyl, —C(O)—C1 fluoroalkyl, —C(O)—(CH2)2—C(O)—NR15bNR15b, —C(O)—CH2—C(O)—NR15bNR15b, —C(O)—NR15b—(CH2)m1—Ar, —C(O)—NR15b—Het, —C(O)—NR15b—C1-6alkyl, —C(O)—NR5aR5b, —S(O)2—(CH2)m2—Ar, —S(O)2-Het, —S(O)2—C1-6alkyl, or —CH2—Ar; or R4 and R5 taken together are —(CH2)p1—, —(CH2)2—X5—(CH2)2—, —C(O)—(CH2)p2—, —C(O)—N(R15)—(CH2)p3—; or NR4R5 is of sub-formula (y), (y1), (y2) or (y3). The invention provides the use of the compounds as inhibitors of phosphodiesterase type IV (PDE4) and/or for the treatment and/or prophylaxis of inflammatory and/or allergic diseases such as COPD and the like.
Synthesis of 3-methylisoxazole-5-Carboxamides and 5-[(1H-pyrazol-1-yl)carbonyl]-3-methylisoxazoles
Martins, Marcos A.P.,Neto, Marcelo,Sinhorin, Adilson P.,Bastos, Giovani P.,Zimmermann, Nilo E.K.,Rosa, Adriano,Bonacorso, Helio G.,Zanatta, Nilo
, p. 425 - 433 (2007/10/03)
The one-pot synthesis of six 3-methylisoxazole-5-carboxamides 2 [where the N-substituents are R1 = H, Me and R2 = PH, CH2Ph, n-Bu, C(CH3)2Et, 3-methylisoxazol-5-yl] and twelve 5-[(1H-pyrazol-1-yl)carb
Synthesis and in vitro activity of new oxazolidinone antibacterial agents having substituted isoxazoles
Pae, Ae Nim,Kim, Hye Yeon,Joo, Hyun Jin,Kim, Bo Hyung,Cho, Yong Seo,Choi, Kyung Il,Choi, Jung Hoon,Koh, Hun Yeong
, p. 2679 - 2684 (2007/10/03)
Two series of oxazolidinone derivatives having substituted isoxazoles were synthesized and tested for antibacterial activities against several Gram-positive strains including the resistant strains of Staphylococcus and Enterococcus, such as MRSA, CRSA, MSSA and VRE. Some of them showed in vitro activities (MIC) comparable or superior to the reference compound vancomycin.
Synthesis and structure-activity relationships of fused imidazopyridines: A new series of benzodiazepine receptor ligands
Takada, Susumu,Sasatani, Takashi,Chomei, Nobuo,Adachi, Makoto,Fujishita, Toshio,Eigyo, Masami,Murata, Shunji,Kawasaki, Kazuo,Matsushita, Akira
, p. 2844 - 2851 (2007/10/03)
2-Arylimidazo[4,5-c]quinolines and analogous fused imidazopyridines were synthesized and evaluated as benzodiazepine receptor ligands. Affinity to the receptors was greatly affected by the bulkiness of the aryl group at the 2- position, compared to the pyrazoloquinolines such as CGS-9896. Derivatives with an isoxazole moiety at the 2-position showed high binding affinity and in vivo activity. In the imidazo[4,5-c]quinoline series, substitution at the 6-position decreased or abolished activity. Most derivatives with an unsubstituted isoxazolyl group showed antagonist or inverse agonist activity except for the 7-halo analogues, which exhibited agonist activity. On the other hand, 5-methylisoxazol-3-yl or 3-methylisoxazol-5-yl derivatives generally exhibited agonist activity. A similar substitution effect on the isoxazole moiety was observed in the imidazopyridines fused with a nonaromatic ring. From the detailed pharmacological evaluation, S-8510, 2- (3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridine monophosphate, possessing weak inverse agonist activity was selected as a therapeutic candidate for the treatment of some symptoms of senile dementia.
Synthesis of Isoxazole-Containing β-Triketones of the Cyclohexane Series
Rubinov, D. B.,Rubinova, I. L.,Akhrem, A. A.
, p. 386 - 389 (2007/10/03)
Condensation of 4-methyl-3-penten-2-one with methyl 3-methyl-5-isoxazolylacetate results in formation of 4-(3-methyl-5-isoxazolyl)-5,5-dimethylcyclohexane-1,3-dione, whose acylation with propionyl and butyryl chlorides and methyl ω-chloroformylpentanoate yields corresponding 2-acylcyclohexane-1,3-diones in overall yields of 70-75percent.Reactions of cyclohexane-1,3-diones with 3-methylisoxazole-5-carbonyl chloride yield β-triketones containing isoxazole ring in the side acyl chain.
