From HTS to Market: the Discovery and Development of Maraviroc, a CCR5 Antagonist for the Treatment of HIV - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 198

Table 9.6 Balancing potency, microsomal stability and hERG anity across a
range of amides containing a 1,3,4-triazole

O

NH

N R

hERG
binding at
300 nM

Binding
IC 50 nM

AV
IC 90 nM

HLM
T 1/2 min Compound R logD

25 27 120 0% 4120 0.9

O

Pr n 26 5 1.3 0% 95 1.5

27 5 14 14% 4120 1.8

F 3 C

28 cyclopentyl 5 0.2 0% 21 2.1

29 0.2 0.7 0% 22 2.0

F

F

9.10 Profiling Maraviroc
Despite the low levels of activity of 29 in the hERG binding assay, it was
further profiled in both the patch-clamp assay (no activity at 200 nM) and in
dog-isolated Purkinje fibres. Finally, it was studied in the conscious dog, and no
effects were seen at 179 nM free plasma concentrations (4100-fold predicted
levels required for ecacy). 33
Compound 29 was also profiled against a wide range of targets in vitro and
showed no significant activity at concentrations up to 10 mM. Importantly, it
also retained a lack of activity against CYP P450s (IC 50 values450 mM),
affording it a significant advantage over existing HIV therapies. 50
When tested in vivo, it demonstrated a modest PK profile in rat (absorption
23%, bioavailability 6%, t 1/2 ¼ 0.9 h) and dog (absorption 70%, bioavailability
42%, t 1/2 ¼ 2.3 h). It displayed limited tissue distribution (V D ¼ 6.5 and
4.3 L kg 1 in rat and dog, respectively), commensurate with a moderately
lipophilic weak base (pK a ¼ 7.7). In human liver microsomes, compound 29 was