TYROSINE KINASE INHIBITORS .11. SOLUBLE ANALOGS OF PYRROLOQUINAZOLINES AND PYRAZOLOQUINAZOLINES AS EPIDERMAL GROWTH-FACTOR RECEPTOR INHIBITORS - SYNTHESIS, BIOLOGICAL EVALUATION, AND MODELING OF THE MODE OF BINDING
Bd. Palmer et al., TYROSINE KINASE INHIBITORS .11. SOLUBLE ANALOGS OF PYRROLOQUINAZOLINES AND PYRAZOLOQUINAZOLINES AS EPIDERMAL GROWTH-FACTOR RECEPTOR INHIBITORS - SYNTHESIS, BIOLOGICAL EVALUATION, AND MODELING OF THE MODE OF BINDING, Journal of medicinal chemistry, 40(10), 1997, pp. 1519-1529
A new route to N-1-substituted pyrazolo- and pyrroloquinazolines has b
een developed from the known quinazolones 19 and 23, via conversion to
the corresponding thiones, S-methylation to the thioethers, N-1-alkyl
ation, and coupling with 3-bromoaniline. C-S-Substituted pyrroloquinaz
olines were prepared by Mannich base chemistry. A series of compounds
bearing solubilizing side chains at these positions has been prepared
and evaluated for inhibition of the tyrosine kinase activity of the is
olated epidermal growth factor receptor (EGFR) and of its autophosphor
ylation in EGF-stimulated A431 cells. Several analogues, particularly
C-3-substituted pyrroloquinazolines, retained high potency in both ass
ays. A model for the binding of the general class of 4-anilinoquinazol
ines to the EGFR was constructed from structural information (particul
arly for the catalytic subunit of the cAMP-dependent protein kinase) a
nd structure-activity relationships (SAR) in the series. In this model
, the pyrrole ring in pyrroloquinazolines (and the 6- and 7-positions
of quinazoline and related pyridopyrimidine inhibitors) occupies the e
ntrance of the ATP binding pocket of the enzyme, with the pyrrole nitr
ogen located at the bottom of the cleft and the pyrrole C-3 position p
ointing toward a pocket corresponding to the ribose binding site of AT
P. This allows considerable bulk tolerance for C-3 substituents and le
sser but still significant bulk tolerance for N-1 substituents. The ob
served high selectivity of these compounds for binding to EGFR over ot
her similar tyrosine kinases is attributed to the 4-anilino ring bindi
ng in an adjacent hydrophobic pocket which has an amino acid compositi
on unique to the EGFR. The SAR seen for inhibition of the isolated enz
yme by the pyrazolo- and pyrroloquinazolines discussed here is fully c
onsistent with this binding model. For the N-1-substituted compounds,
inhibition of autophosphorylation in A431 cells correlates well with i
nhibition of the isolated enzyme, as seen previously for related pyrid
opyrimidines. However, the C-S-substituted pyrroloquinazolines show un
expectedly high potencies in the autophosphorylation assay, making the
m of particular interest.