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Titolo:
S(+)-4-(1-phenylethylamino)quinazolines as inhibitors of human immunoglobuline E synthesis: Potency is dictated by stereochemistry and atomic point charges at N-1
Autore:
Berger, M; Albrecht, B; Berces, A; Ettmayer, P; Neruda, W; Woisetschlager, M;
Indirizzi:
Novartis Forschungsinst, A-1235 Vienna, Austria Novartis Forschungsinst Vienna Austria A-1235 st, A-1235 Vienna, Austria
Titolo Testata:
JOURNAL OF MEDICINAL CHEMISTRY
fascicolo: 18, volume: 44, anno: 2001,
pagine: 3031 - 3038
SICI:
0022-2623(20010830)44:18<3031:SAIOHI>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
FC-EPSILON-RI; EPIDERMAL LANGERHANS CELLS; HUMAN RECOMBINANT INTERLEUKIN-4; RECEPTOR TYROSINE KINASE; IGE GERMLINE PROMOTER; SOLUBLE IL-4 RECEPTOR; IN-VIVO TREATMENT; COMBINATORIAL SYNTHESIS; ALLERGEN PRESENTATION; B-CELLS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
43
Recensione:
Indirizzi per estratti:
Indirizzo: Ettmayer, P Novartis Forschungsinst, Brunnerstr 59, A-1235 Vienna, AustriaNovartis Forschungsinst Brunnerstr 59 Vienna Austria A-1235 a
Citazione:
M. Berger et al., "S(+)-4-(1-phenylethylamino)quinazolines as inhibitors of human immunoglobuline E synthesis: Potency is dictated by stereochemistry and atomic point charges at N-1", J MED CHEM, 44(18), 2001, pp. 3031-3038

Abstract

Since the pathogenesis of allergic diseases is associated with elevated levels of immunoglobulin E (IgE), we developed a high throughput reporter gene assay in a human B-cell line to screen for low molecular weight IgE inhibitory compounds. Monitoring the IL-4 driven IgE-germline promoter activity (IgE-GLP), we discovered 4-(1-phenylethylamino)qinazolines as potent inhibitors of IgE-germline gene expression. Testing of the individual enantiomers(1, 2) revealed that only the S(+) enantiomer 1 was active. A cell viability assay done in the same cell line in parallel discriminated the dose-dependent inhibition from a general antiproliferative effect. The observed correlation of the inhibitory potencies found in the reporter gene assay with those measured by IgE-ELISA in primary human splenocytes provided evidence that the blockade of IgE synthesis is the direct consequence of IgE-germlinegene inhibition, thereby validating the reporter gene assay. Parallel synthesis in solution rapidly provided a series of analogues of compound 1 withmodifications in the phenethylamine side chain and the quinazoline core for SAR studies. Increasing the lipophilicity of the arylalkylamine moiety yielded S(+)-4-(1-(2-naphthyl)ethylamino)quinazoline (6) as the most potent inhibitor (IC50 of 14 nM) while the R(-) enantiomer was again found to be inactive. Within the set of S enantiomers, quantum mechanical calculations revealed that the IgE inhibitory activity can be quantitatively described by the charge at N-1 of the heterocyclic core and to a lesser extent by the molar refractivity. These results demonstrate the importance of electron-deficient fused 4-aminopyrimidines and lipophilic side chains for biological activity. The strong preference for the S configuration of the phenethylamineside chain is remarkable insofar as biological activity for fused 4-(1-phenylethylamino)pyrimidines has been published for the R enantiomers only (EGFR tyrosine kinase inhibition).

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/03/20 alle ore 01:57:49