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 204

Table 9.8 Replacing the tropane bridge in maraviroc with a side-chain a-methyl group resulted in similar profiles both in vitro
and in vivo. 82

O

F

N

N

N N N N N N

F

N N

N N N

c

29 38 39

Fusion IC 50 (nM) 0.2 0.5 3.1

AV IC 90 (nM) 2.8 1.8 2.6

log D 1.9 2.2 3.0

HLM t 1/2 (min) 22 12 15

MDCK a

Papps ¼ 0.5; er ¼ 2 Papps ¼ 0.9; er ¼ 21 Papps ¼ 23; er ¼ 2

hERG IC 50 (mM) 410 410 410

CYP2D6 inhib b

23% @ 3 mM 430 mM 430 mM

CYP3A4 inhib b

23% @ 3 mM 430 mM 3.4 mM

Rat PK
Bioavailability 6% 6% 57%

Cl (mLmin 1 kg 1 ) 74 92 30

V D (L kg 1 ) 6.5 10 2.5

t 1/2 (h) 0.9 1.3 1.0

a MDCK ¼ flux through Madin-Darby canine kidney cells; 74 Papps ¼ AB (10 6 cm s 1 ), er ¼ eux ratio A-B/B-A.
b Inhibition of turnover of cytochrome isozyme.
c Most active stereoisomer; absolute configuration not determined.