Download (8Mb) - Etheses - Saurashtra University

this series of compounds against the HIV PR dimer revealed that a and b were
extremely potent inhibitors Ki = 0.023 and 0.012 nM respectively. The compounds
were also able to inhibit viral replication in vitro as measured by the ability of the
compounds to inhibit RNA synthesis by 90% (a) IC90 = 13.2 nM; (b) IC90 = 26.2 nM).
Interestingly, QSAR on this series of cyclic ureas suggested the optimum lipophilicity
for protease inhibition (ClogP = 4.4) is different from the inhibition of viral
replication (ClogP = 6.36) as revealed by the reversal of Ki and IC90 selectivities for
(a) and (b). This makes it difficult to optimize both parameters within the same
molecule, but suggests that while (a, b) display the same hydrogen bonding pattern at
the terminal urea, the lipophilicity disparity between the 2-aminoimidazole and the
benzimidazole has a significant effect on their pharmacokinetic profile. With these
results, (a) and (b) were advanced for pharmacokinetic studies in female Beagles. As
seen in the pharmacokinetic profiles (Fig. 1.11.3) the decreased lipohilicity of (b) had
a significant impact on the clearance (CL) and half-life (t1/2) of the compound,
advancing its candidacy based on this improved PK profile.
N
NH
H
N
Ph HO OH Ph
O
N
O
N
NH 2
N
NH
H
N
a b
Fig.- 1.11.3 Unsymmetrical HIV PR inhibitors.
Parameter a b
Ki (nM) 0.023 0.012
IC90 (nM) 13.2 26.2
Dose (mg/kg) 5.0 5.0
CL, L/h/kg 0.8 0.5
Vss (L/Kg) 1.0 4.0
T1/2 (h,iv) 0.9 5.6
Ph HO OH Ph
Table-1.13.1: Pharmacokinetic profiles of HIV PR inhibitors
O
N
O
N
NH 2