The Discovery of GS-9131, an Amidate Prodrug of a Novel Nucleoside Phosphonate HIV Reverse Transcriptase Inhibitor - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 217

10.1.2 Target Profile for a Novel RT Inhibitor
The success of HAART therapy has increased life expectancy among infected
patients to 420 years post diagnosis, in effect transforming HIV into a man-
ageable life-long disease. In this context, the durability of therapy in an aging
population can be limited by drug resistance, side effects due to chronic use,
and drug-drug interactions. Therefore, more effective and convenient fixed-
dose qd regimens are highly desirable in continuing the fight against HIV. New
fixed-dose qd regimens combining 2 and 3 with HIV protease and HIV inte-
grase inhibitors are being evaluated clinically. 6 The established role of
N(t)RTIs as the backbone of choice in HAART therapy supports the devel-
opment of new N(t)RTIs that can be combined with the existing treatment
options or newer drugs in development. With this aim in mind, a program was
initiated toward identifying a novel N(t)RTI that would have (i) an oral qd
dosing schedule; (ii) an excellent resistance profile effective against clinically
observed RT mutants, especially those that reduce susceptibility to 2 and 3; (iii)
a low potential for long-term toxicities; and (iv) the ability to be combined with
other N(t)RTIs in HAART therapy.
10.1.3 Mechanism of Action of N(t)RTIs
A detailed understanding of the mechanism by which N(t)RTIs inhibit HIV RT
is necessary to fully appreciate the strategy employed toward designing a
new N(t)RTI drug. Consider first the NRTIs, which are neutral species at
physiological pH and cross into cells passively or via nucleoside transporters
(Figure 10.2).
The target cells for HIV inhibitors are cells in which the virus is replicating,
primarily CD4 þ memory T-cells and macrophages in lymph nodes and in
peripheral blood. Inside target cells, kinases anabolise the nucleoside to its
active triphosphate metabolite, for example 3-TP, whereas phosphorylases
catabolise degradation back to the nucleoside 3. The metabolite 3-TP is the
active species and competes with the natural intracellular pools of deoxy-
nucleotide substrate, in this case dCTP (10), for incorporation into the growing
DNA polymerase chain. Inspection of the chemical structures of the N(t)RTIs
2-7 highlights the absence of a 3 0 - hydroxyl group on the deoxyribose ring or
equivalent group of each inhibitor, unlike the natural substrates 9 or 10, for
example. This is an essential feature of all the N(t)RTI drugs, such that after a
single incorporation of the inhibitor into the growing DNA, the inhibitor
causes chain termination, that is, unless the blocking nucleotide can be excised
from the end of the growing chain. Thus, the mechanism of action for the
nucleoside inhibitors is passive or active transport into cells, activation by three
intracellular kinases to the triphosphate, incorporation by HIV RT into the
growing DNA, and chain termination of the DNA polymerization process.
In contrast, the N(t)RTIs, exemplified by nucleoside phosphonate 1, present
some unique features that set them apart. Phosphonate 1, bearing an adenine
nucleobase, is essentially a bioisostere of deoxyadenosine monophosphate, the