128018-90-6Relevant academic research and scientific papers
Configurationally stable analogs of styrylxanthines as A(2A) adenosine receptor antagonists
Mueller,Schobert,Hipp,Geis,Frobenius,Pawlowski
, p. 709 - 719 (1997)
Configurationally stable analogs of the potent, A(2A)-selective adenosine receptor (AR) antagonist 3,7-dimethyl-1-propargyl-8-styrylxanthine (8-styryl-DMPX, 3) were synthesized and investigated in radioligand binding assays for affinity to the high-affinity A1- and A(2A)-AR subtypes of rat brain. All derivatives prepared, including compounds in which the styryl double bond was replaced by a cyclopropane ring or a triple bond, or in which it was integrated into a (hetero) cyclic ring system, were less potent and less selective compared to the parent compound 3. The best compound of the present series was 8-(phenylethynyl)-DMPX (21), exhibiting a K(i) value at A(2A)-AR of 300 nM and a > 10-fold selectivity versus A1-AR. In view of its configurational stability, 21 may be an interesting lend compound for the development of more potent A(2A) antagonists by introducing appropriate substituents in the phenyl ring. Based on conformational analysis of 8-styrylxanthine and 8-(2-naphthyl)xanthine derivatives, it is hypothesized that the bioactive conformation of (E)-8-styryl substituents with regard to the imidazole ring of the xanthine nucleus at A(2A)-AR may be nearly coplanar and cisoid, and may differ from the bioactive conformation of such xanthine derivatives at A1-AR.
A multidisciplinary study of 3-(β-D-glucopyranosyl)-5-substituted-1,2,4-triazole derivatives as glycogen phosphorylase inhibitors: Computation, synthesis, crystallography and kinetics reveal new potent inhibitors
Kun, Sándor,Begum, Jaida,Kyriakis, Efthimios,Stamati, Evgenia C.V.,Barkas, Thomas A.,Szennyes, Eszter,Bokor, éva,Szabó, Katalin E.,Stravodimos, George A.,Sipos, ádám,Docsa, Tibor,Gergely, Pál,Moffatt, Colin,Patraskaki, Myrto S.,Kokolaki, Maria C.,Gkerdi, Alkistis,Skamnaki, Vassiliki T.,Leonidas, Demetres D.,Somsák, László,Hayes, Joseph M.
, p. 266 - 278 (2018)
3-(β-D-Glucopyranosyl)-5-substituted-1,2,4-triazoles have been revealed as an effective scaffold for the development of potent glycogen phosphorylase (GP) inhibitors but with the potency very sensitive to the nature of the alkyl/aryl 5-substituent (Kun et al., Eur. J. Med. Chem. 2014, 76, 567). For a training set of these ligands, quantum mechanics-polarized ligand docking (QM-PLD) demonstrated good potential to identify larger differences in potencies (predictive index PI = 0.82) and potent inhibitors with Ki's 10 μM (AU-ROC = 0.86). Accordingly, in silico screening of 2335 new analogues exploiting the ZINC docking database was performed and nine predicted candidates selected for synthesis. The compounds were prepared in O-perbenzoylated forms by either ring transformation of 5-β-D-glucopyranosyl tetrazole by N-benzyl-arenecarboximidoyl chlorides, ring closure of C-(β-D-glucopyranosyl)formamidrazone with aroyl chlorides, or that of N-(β-D-glucopyranosylcarbonyl)arenethiocarboxamides by hydrazine, followed by deprotections. Kinetics experiments against rabbit muscle GPb (rmGPb) and human liver GPa (hlGPa) revealed five compounds as potent low μM inhibitors with three of these on the submicromolar range for rmGPa. X-ray crystallographic analysis sourced the potency to a combination of favorable interactions from the 1,2,4-triazole and suitable aryl substituents in the GP catalytic site. The compounds also revealed promising calculated pharmacokinetic profiles.
