Non-Peptide Glycoprotein IIb/IIIa Antagonists. 11. Design and in Vivo
Evaluation of 3,4-Dihydro-1(1H)-isoquinolinone-Based Antagonists and Ethyl
Ester Prodrugs
posted on 1996-11-08, 00:00authored byJohn H. Hutchinson, Jacquelynn J. Cook, Karen M. Brashear, Michael J. Breslin, Joan D. Glass, Robert J. Gould, Wasyl Halczenko, Marie A. Holahan, Robert J. Lynch, Gary R. Sitko, Maria T. Stranieri, George D. Hartman
The structure−activity relationship of a series of
orally active glycoprotein IIb/IIIa antagonists
containing a nitrogen heterocycle grafted onto a
3,4-dihydro-1(1H)-isoquinolinone core is
described. These compounds are structurally novel analogs of the
progenitor compound 1 (L-734,217,
[[3(R)-[2-(piperidin-4-yl)ethyl]-2-oxopiperidinyl]acetyl]-3(R)-methyl-β-alanine)
in which
the lactam chiral center has been removed. The 4-piperazinyl- and
4-piperidinyl-substituted
3,4-dihydro-1(1H)-isoquinolinones were found to be optimal
for in vitro potency. In addition,
substitution at the 3-position of the β-amino acid enhanced potency
with the 3-pyridyl and
3-ethynyl analogs being the most potent prepared. Attempts to
improve the in vivo profile of
these compounds focused on modification of the physical properties.
Ester prodrugs were
prepared to increase the lipophilicity and remove the zwitterionic
nature of the antagonists.
The prodrug approach, coupled with the arylpiperazine terminus
(pKa = ∼9.0), afforded
moderately basic and relatively nonpolar compounds. The acid
N-[[7-(piperazin-1-yl)-3,4-dihydro-1(1H)-oxoisoquinolin-2-yl]acetyl]-3(S)-ethynyl-β-alanine,
6d (L-767,679), is a potent
fibrinogen receptor antagonist able to inhibit the ADP-induced
aggregation of human gel-filtered
platelets with an IC50 of 12 nM. Although
6d is orally active based on the results of an ex
vivo
dog assay at 0.3 mg/kg, the ethyl ester prodrug of this compound,
19 (L-767,685), is better
absorbed at this dose than 6d. Upon oral dosing, the
ester 19 is converted to 6din vivo in
dog
with an estimated oral systemic availability of >17% (0−8 h,
AUC19po/AUC6div).
In addition,
studies in monkey at an oral dose of 1 mg/kg show that 19
affects the complete inhibition of
the ex vivo platelet aggregation in response to ADP between
2 and 8 h postdose with the level
of inhibition remaining at 40% at 12 h postdose. This level of
activity was superior to that
observed for 6d and 1 at the same dose.
Using ex vivo ADP-induced aggregation data
from
rhesus monkey (n = 2, 0−8 h using the
AUC19po/AUC6div),
the estimated systemic oral
availability of 6d when dosed as 19 is
32%.