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 191

Table 9.2 Adding a bridge across the piperidine; minimised energy

conformations

O O O

N H N H

N H

N N N

N N

N N N

N

8 9 10

Binding IC 50 ¼ 4 nM Binding IC 50 ¼ 6 nM Binding IC 50 ¼ 2nM

AV IC 90 ¼ 440 nM AV IC 90 ¼ 4nM AVIC 90 ¼ 5nM

While heterocycles both reduced lipophilicity and appeared to be tolerated
(e.g. 6), they were synthetically less accessible than simple amides and carba-
mates (e.g. 4 and 7), which also possessed good ligand eciency (40.3). Even
more encouragingly, 7 demonstrated antiviral activity (AV IC 90 ¼ 0.4 mM) and
consequently a wider range of less lipophilic amides were prepared in a parallel
manner. 36 This work culminated in the identification of cyclobutyl derivative 8
(S enantiomer), which demonstrated excellent ligand eciency (0.36) and
antiviral activity (Table 9.2).
Compound 8 was screened across a wide panel of targets to identify potential
selectivity issues. Some CYP2D6 activity was observed (IC 50 ¼ 5 mM),
prompting a fresh analysis of the CYP binding model. Molecular modelling
suggested the central amine could coordinate Asp301, which literature had
concluded was critical for activity (Figure 9.4 shows a model of the binding
of 8). 37 Removal of this basic centre was not investigated, as SAR suggested it
was essential for CCR5 binding potency (a conclusion later supported by the
commonality of a central basic amine in other CCR5 antagonists; Figure 9.2).
Instead, attempts to modulate the pK a , sterically encumber the basic centre or
present it differently were undertaken. 27,36 The most effective of these strategies
was to add a bridge across the piperidine to give a tropane ring (Table 9.2).

9.7 Exploration of the Tropane Core
The addition of this bridge (from 8 to 9 and 10) was pivotal in the development
of this series. In a single step, it completely ablated activity against CYP2D6
with negligible impact on CCR5 binding anity (no activity against CYP2D6
at 2.3 mM). Most dramatically, it increased antiviral activity by two orders of