title: S(+)-4-(1-Phenylethylamino)quinazolines as inhibitors of human immunoglobulin E synthesis: potency is dictated by stereochemistry and atomic point charges at N-1.
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-germline gene inhibition, thereby validating the reporter gene assay. Parallel synthesis in solution rapidly provided a series of analogues of compound 1 with modifications 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 (IC(50) 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 phenethylamine side 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).
authors.affiliation: Novartis Forschungsinstitut, Brunnerstrasse 59, Vienna A-1235, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Berger
authors.forename: B
authors.initials: B
authors.lastname: Albrecht
authors.forename: A
authors.initials: A
authors.lastname: Berces
authors.forename: P
authors.initials: P
authors.lastname: Ettmayer
authors.forename: W
authors.initials: W
authors.lastname: Neruda
authors.forename: M
authors.initials: M
authors.lastname: Woisetschläger
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001402:B-Lymphocytes / Q000378:metabolism; D015152:Blotting, Northern; D019013:CD40 Antigens / Q000276:immunology; D002460:Cell Line; D003864:Depression, Chemical; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D017930:Genes, Reporter; D005854:Germ Cells; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis* / Q000235:genetics; D015847:Interleukin-4 / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015203:Reproducibility of Results; D013154:Spleen / Q000166:cytology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D011799:Quinazolines; D015847:Interleukin-4; D007073:Immunoglobulin E; D014443:Tyrosine; D008156:Luciferases; D066246:ErbB Receptors