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 224

Table 10.3 Antiviral activity, mitochondrial toxicity, and resistance profile of novel N(t)RTIs

NH 2

NH 2

N

N

N

OH

N

OH

HO

OH

P O N

N

N O P

N

O

O

O

O 22

21

F

.

6TAMs c
fold
resistance

M184V c
fold
resistance

K65R c
fold
resistance

Host DNA Polymerase IC 50 (mM)

wt HIV a
EC 50 (mM)

MTC 50 b
CC 50 (mM)

wt RT
IC 50 (mM) Cpd a b g

1 0.38 61 51 4300 3.6 (1.5) 4300 8.8 (3.7) 0.7 (0.2) 4.3 (1.5)

15 0.60 - - - 2.1 (1.0) 3.6 (1.5) 2.9 (1.0) 0.9 (0.6) 2.9 (1.1)

21 - - - - 5.9 (0.3) 4300 14 (2.3) 11 (4.8) 3.6 (2.0

22 1.9 44 4175 4300 10.6 (2.4) 4300 4.3 (0.4) 0.8 (0.1) 1.1 (0.2)

a Values are results of at least two experiments; standard deviation is given in parentheses.
b Concentration required to reduce mtDNA by 50%.
c Resistance determined in MT-2 cell lines.