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 220

NH 2

N

N

O O

O N

N

P O

H

O

11

Figure 10.3 Monoamidate prodrug of 1 (GS-7340).

improved antiviral response over 14 days dosing. 10 The precedent established
by 11 was of great significance since it was expected that a similar prodrug
approach could be applied to a second-generation nucleoside phosphonate,
leading to the tantalizing prospect of a new N(t)RTI preferentially targeted to
PBMCs.

10.2.2 Design, Evaluation, and Modeling of Novel N(t)RTIs
Lead compounds for the new program were identified by examining the lit-
erature for nucleoside phosphonate analogs. 11-17 Initially, a number of new
analogs of 1 were made, including modified nucleobases, extending the acyclic
two carbon chain between the nucleobase and the oxygen atom, and changing
the substituent on the two-carbon chain. Unfortunately, although many ana-
logs were effective at inhibiting HIV in the antiviral cell assay, no new analog
demonstrated a significantly improved resistance profile and cell-based toxicity
profile compared to 1. Focus then shifted to the more synthetically demanding
cyclic analogs using the reported 2 0 ,3 0 -dideoxydidehydro (d4) analogs, d4TP
(12) and d4AP (15), as leads. 17 Selected analogs and their antiviral activities are
shown in Table 10.1.
Replacing the thymine base of 12 with alternative pyrimidine bases, such as
uridine analog 13 or 5-fluorouridine analog 14, clearly reduced antiviral
activity. 18,19 It was important to understand the reason for the reduced cell-
based antiviral activity of the pyrimidines 12-14 compared to adenine 15, since
this could be due to (i) differences in cell penetration of the diacids, (ii) dif-
ferences in intracellular metabolism to the active diphosphates, or (iii) differ-
ences in the ability of the active diphosphates to inhibit RT. Therefore, for
many analogs the diphosphate metabolites were prepared and their inhibition
of RT determined in vitro. This strategy provided valuable information con-
cerning the structure-activity relationship (SAR) of the N(t)RTIs and allowed
more rational design of target molecules. For example, thymidine 12-DP had a
greater RT potency than adenine 15-DP despite its 410-fold reduced antiviral
potency, suggesting that 12 lacked antiviral activity due to deficiencies in cell