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 190

would need addressing while establishing SAR. This immediately flagged two
key issues. Strong activity was observed against the cardiac hERG (human
ether-a-go-go) potassium ion channel (IC 50 o 316 nM). Activity against the
hERG channel was particularly concerning, given the risk of developing a
potentially fatal arrhythmia through prolongation of the QT interval, an effect
that had lead to the withdrawal of terfenadine and cisapride. 34 In addition, 1
also exhibited strong inhibition of the P450 cytochrome 2D6 isoform
(IC 50 ¼ 40 nM). Inhibition of this enzyme would affect drug levels for com-
pounds metabolised by CYP2D6, which could not be tolerated in a compound
likely to be administered in combination with other agents. In short, a reduc-
tion in lipophilicity, together with a concomitant increase in potency, decreased
hERG anity and reduced CYP2D6 inhibition, would all have to be rapidly
demonstrated to give confidence for further investment in this series.
Modelling of the CYP2D6 binding pocket suggested a binding mode in
which the pyridyl nitrogen could coordinate to the heme; this has often been
seen with nitrogen-containing heterocycles. 35 Replacing the pyridyl nitrogen
with a carbon would thus be expected to reduce CYP2D6 inhibition, and from
2 was a change expected to maintain CCR5 binding anity. This substitution
gave 3 (Table 9.1), which did indeed show a significant reduction in anity for
CYP2D6 (IC 50 ¼ 710 nM) and an increase in CCR5 binding.
Reduction in lipophilicity remained critical for this series and the diphenyl
methylene moiety was targeted. It was proposed to remove one of the phenyl
rings and replace it with either a polar heterocycle (should aromaticity be
required) or just a small group (should a conformational constraint be su-
cient). Table 9.1 shows a selection of these compounds.

Table 9.1 Replacing one phenyl with amino derivatives

R

N

N

N

binding IC 50 (LE a ) clog P b Compound R

3 Ph 1.8 nM (0.38) 5.7

4 NHBoc 40 nM (0.30) 4.8

5 NH 2 7.9 mM (0.27) 3.0

6 1,3,4-triazolyl 70 nM (0.32) 2.1

7 NHCOPh 13 nM (0.31) 4.8

a LE ¼ ligand eciency (see eqn 1).
b clog P ¼ calculated log P.