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 195

rates approximately equal to liver blood flow (Cl ¼ 49mLmin 1 kg 1 ). Robust
clearance combined with a modest volume of 4.9 L kg 1 resulted in an
elimination t 1/2 of 1.2 h. Reducing the lipophilicity seemed to offer the best
chance of improving metabolic stability. Given the molecular weight, a strategy
of removing lipophilicity was undertaken rather than adding polarity. 36 Such
an approach was supported by Lipiniski's analysis of the probability of
achieving good oral bioavailability with compounds with a molecular weight
under 500. 46 The benzimidazole fragment became a focus for this phase of the
optimisation.
9.8 Optimising the Heterocyclic Group
Previous work within the piperidine series around 8 had highlighted a number
of alternative heterocycles that retained ecacy (Table 9.4). 43
Initially the phenyl was considered important and amide and heterocyclic
expressions that retained a phenyl ring were prepared (16-19); these tended to
show similar levels of binding. However, when the phenyl was replaced with
smaller substituents, potency (and ligand eciency) was largely retained (cf. 17
and 20). This observation was then applied to the tropane core, and a range of
five-membered ring aromatic heterocycles prepared and resulted in the identi-
fication of the 1,3,4-triazoles. Both exo-andendo-1,3,4-triazoles were prepared,
with potency showing little sensitivity to the substituents but favouring the exo
analogues (21-24, Table 9.5).
Compound 23 showed a good balance of antiviral activity and HLM stability
and was thus profiled in vivo. Bioavailability was low in the rat as a result of
poor absorption (only 20%), but improved absorption in the dog (480%)
resulted in a bioavailability of 43%. Allometric scaling from rat gave a human
dose prediction of 350mg bid, while the superior dog PK profile led to a human
dose prediction of 100mg bid. However, the binding anity for the hERG ion
channel appeared significant, and so 23 was further profiled in a cellular patch-
clamp assay, and then in dog Purkinjie fibre. These three assays were in
agreement: the risk of QT prolongation from plasma levels likely to be
necessary for antiviral effects precluded the further development of this
compound. 43
9.9 Closing in on Maraviroc
Despite the hERG activity shown by 23, the project was encouraged by the
human dose-predictions and the knowledge that modifications to the amide
could attenuate hERG ion channel activity. Parallel chemistry allowed rapid
access to an array of amides, a selection of which is shown in Table 9.6.
Carbon homologation of 23 gave cyclopentyl analogue 28, with increased
antiviral ecacy, but at the cost of metabolic stability. The tetrahydropyranyl
substituent (see 25), which had shown good antiviral activity in the benzimi-
dazole series (15, Table 9.3), lost antiviral activity when applied to the triazoles.