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 232

Table 10.5 The iv and oral pharmacokinetics of selected prodrugs and their separated diastereoisomers

NH 2

NH 2

EtO O

N

N

N N

O

O

P O N P O N

N

N H

O

O O

O

NH

F F

EtO O

31 32

.

Oral PBMC
C max 22-DP
(mM)

IV clearance
(L h 1 kg 1 )

IV PBMC C max
22 a (mM)

Loading
eciency b

Oral plasma
prodrug %F Cpd Human Cat A

11 35 000 2.23 (0.25) - 0.58 21 (3) -

29d 17 355 3.22 (1.17) 0.94 (0.26) 0.05 - -

30d 29 655 3.70 (0.30) 22 (7.3) 1.94 2.6 (0.9) -

30h 18 150 2.76 (0.88) 21 (5.3) 0.62 - -

30g 7280 1.71 (0.41) 17 (1.5) 0.47 12 (3.5) 7.8 (3.0)

9.8 (6.8) c 31 645 - - - 5.2 (1.0)

18 (13) c 32 12 371 - - - 9.0 (2.3)

a Quantity of diacid 22 measured after dephosphorylation of samples with calf intestinal phosphatase.
b Dose normalized.
c Estimated based on iv parameters for isomeric mixture.