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 192

Figure 9.4 Model of the interaction of 8 with CYP2D6.
magnitude, highlighting a disconnect between binding and antiviral activity.
This discrepancy has also been observed by a number of other groups. 38 There
are a number of possible reasons for this disconnect, including differences in the
off-rates of inhibitors from the CCR5 receptor, or the engagement of different
binding sites on CCR5 for chemokines, small molecules and the viral protein.
Initially, it had not been expected that both endo and exo isomers would show
such similar levels of activity, but energy-minimised structures show that the
tropane ring can switch from chair to boat conformations to minimise steric
clashes, thereby giving a comparable disposition of substituents (Table 9.2).
Since incorporation of the tropane core represented a key change in che-
motype for the project, 9 and 10 were profiled against a wide range of targets
and submitted to in vitro metabolic stability assays. Unsurprisingly for a
compound with a log D43.6, compound 9 showed poor stability in human
liver microsomes (t 1/2 ¼ 8min). A more pressing concern, however, was the
activity that both compounds showed against the hERG ion channel (9, 99%
inhibition at 1 mM; 10, 80% inhibition at 300 nM). Consequently, a prime
objective for programme became the reduction of hERG activity and
lipophilicity.