Chemistry Reference
In-Depth Information
Table 10.6 Activities of 22 and 32 against different subtypes of HIV-1 clinical
isolates in PBMCs.
EC
50
(mM)
a
UG-92-031
subtype A
B940374
subtype B
LJM
subtype B
BR-92-025
subtype C
UG-92-024
subtype D
Compound
5 (AZT)
0.16
0.31
0.33
0.26
0.13
22 (GS-9148)
12.5
17.6
8.2
5.1
12.6
32 (GS-9131)
0.037
0.030
0.027
0.068
0.023
a
Values are results of at least three experiments.
22 to its active diphosphate metabolite 22-DP peaked at
5 h with a con-
centration exceeding 9.0 mM, a level well above the RT IC
50
of 1.9 mM. Fur-
thermore, and very importantly, metabolite 22-DP persists inside the PBMC
for periods in excess of 24 h, thereby favoring a potential qd dosing regimen for
the prodrug fulfilling a critical aspect of the target profile. Based on these data,
prodrug 32 was chosen as the most promising candidate for preclinical toxi-
cological evaluation. The prodrug 32 was evaluated against many subtypes of
HIV, and the antiviral activity was significantly improved over that of the
diacid 22 and more potent on average than 5 (Table 10.6).
29
The absolute configuration of prodrug isomer 32 was established by crys-
tallography and was the same stereochemistry at phosphorus reported for
monoamidate 11, supporting that Cat A preferentially recognizes a specific
phosphorus isomer of this class of prodrugs.
32
B
10.3.4 Toxicological Evaluation
Selection of the ideal prodrug 32 was followed by extensive evaluation with
respect to potential toxicities and drug-drug interactions that could limit its
clinical utility. N(t)RTIs are known to be renally eliminated by a combination
of glomerular filtration and active tubular secretion.
33
Furthermore, accumu-
lation of this class of compounds in kidney tissue has been observed in several
animal species, and drug-related adverse events as a result of changes in renal
proximal tubule function have been found in patients treated with certain
nucleotide regimens. Studies carried out in vitro established that 22 has reduced
eciency for uptake via renal organic anion transporters hOAT1 and hOAT3
compared to 1, but is still a substrate for the eux pump MRP4, indicating a
low potential for renal accumulation. Consistent with these molecular findings,
the oral administration of [
14
C]-32 to dogs demonstrated limited accumulation
of diacid 22 in kidney tissue. Extended 28-day oral dosing studies were per-
formed in Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys and
established no significant renal findings.
33
The potential also exists for drug-
drug interactions when dosing adenine analog 22 with other adenine-based
nucleos(t)ide inhibitors as part of a combination regimen for HIV patients,
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