PMID- 11520212
OWN - NLM
STAT- MEDLINE
DCOM- 20010927
LR  - 20190710
IS  - 0022-2623 (Print)
IS  - 0022-2623 (Linking)
VI  - 44
IP  - 18
DP  - 2001 Aug 30
TI  - S(+)-4-(1-Phenylethylamino)quinazolines as inhibitors of human immunoglobulin E 
      synthesis: potency is dictated by stereochemistry and atomic point charges at 
      N-1.
PG  - 3031-8
AB  - 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).
FAU - Berger, M
AU  - Berger M
AD  - Novartis Forschungsinstitut, Brunnerstrasse 59, Vienna A-1235, Austria.
FAU - Albrecht, B
AU  - Albrecht B
FAU - Berces, A
AU  - Berces A
FAU - Ettmayer, P
AU  - Ettmayer P
FAU - Neruda, W
AU  - Neruda W
FAU - Woisetschlager, M
AU  - Woisetschlager M
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (CD40 Antigens)
RN  - 0 (Quinazolines)
RN  - 207137-56-2 (Interleukin-4)
RN  - 37341-29-0 (Immunoglobulin E)
RN  - 42HK56048U (Tyrosine)
RN  - EC 1.13.12.- (Luciferases)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/pharmacology
MH  - B-Lymphocytes/metabolism
MH  - Blotting, Northern
MH  - CD40 Antigens/immunology
MH  - Cell Line
MH  - Depression, Chemical
MH  - Enzyme-Linked Immunosorbent Assay
MH  - ErbB Receptors/metabolism
MH  - Female
MH  - Genes, Reporter
MH  - Germ Cells
MH  - Humans
MH  - Immunoglobulin E/*biosynthesis/genetics
MH  - Interleukin-4/pharmacology
MH  - Luciferases/genetics/metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Phosphorylation
MH  - Promoter Regions, Genetic
MH  - Quinazolines/*chemical synthesis/chemistry/pharmacology
MH  - Reproducibility of Results
MH  - Spleen/cytology
MH  - Stereoisomerism
MH  - Structure-Activity Relationship
MH  - Tyrosine/metabolism
EDAT- 2001/08/25 10:00
MHDA- 2001/09/28 10:01
CRDT- 2001/08/25 10:00
PHST- 2001/08/25 10:00 [pubmed]
PHST- 2001/09/28 10:01 [medline]
PHST- 2001/08/25 10:00 [entrez]
AID - jm010888h [pii]
AID - 10.1021/jm010888h [doi]
PST - ppublish
SO  - J Med Chem. 2001 Aug 30;44(18):3031-8. doi: 10.1021/jm010888h.