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 222

Table 10.2 Antiviral activity, RT inhibition, and resistance profile of 4 0 -
modified carbocyclic N(t)RTIs

O

NH 2

N

NH

N

OH

HO

HO

P O N

N O N 18. R = H

19. R = Ethynyl
20. R = Me

O

O

17

R

.

wt HIV a
MT-2
EC 50 (mM)

M184V c
fold
resistance

K65R c
fold
resistance

wt RT b
IC 50 (mM)

MT-2 cell
CC 50 (mM) Compound

1 3.6 (1.5) 41000 0.38 (0.20) 0.7 (0.2) 4.3 (1.5)
15 2.1 (1.0) 41000 0.60 (0.16) 0.9 (0.6) 2.9 (1.1)
17 0.81 (0.4) - - 4.8 (0.1) 0.4 (0.2)
18 52 (13) - - - -
19 16 (9.6) 1450 0.13 (0.10) 430 2.2 (0.5)
20 244 - - - -
a Values are results of at least two experiments; standard deviation is given in parentheses.
b Data for the diphosphophosphonate metabolites.
c Resistance determined in MT-2 cell lines.

addition, carbocyclic d4 analog 7 and the N(t)RTI 18 are also known to be
potent RT inhibitors. 21 Combining these SAR observations resulted in the
proposed target 19,a4 0 -ethynyl-modified carbocyclic d4 adenine analog that
was expected to have a good K65R resistance profile. The carbocyclic d4 core
was employed since it was more synthetically accessible than the d4 ribose core
and allowed for additional analogs, such as the 4 0 -methyl analog 20,tobe
readily prepared. 21 The antiviral activity is shown in Table 10.2 and indicates
that 19 has greater antiviral activity than 18, and the profile toward K65R was
superior to 1. Methyl analog 20 was weakly active, suggesting the methyl group
was too big for the pocket. Unfortunately, 19 demonstrated a very poor
resistance profile toward M184V (430-fold loss), far inferior to 1 and the cyclic
analog 15. Further active-site modeling, in which the wt residue 184 was
mutated to valine, suggested this was probably due to unfavorable steric
interactions with residue Y115 in the M184V RT mutant site. 21 Overall, despite
much investigation of N(t)RTI SAR, compound 15 remained the most pro-
mising lead based on antiviral potency, RT inhibition, and resistance profile,
but could not be pursued because of poor selectivity.

10.2.3 Improving Selectivity Toward HIV RT
Analog 15 has been reported to be an inhibitor of the host mitochondrial DNA
polymerase g and this leads to significant toxicity effects (MTC 50 ¼ 3.6 mM)