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 207

good pharmacokinetic profile (monkey F ¼ 43%, MRT 8 h). 87 Incyte's 45
(INCB-9471) has the potential to become best-in-class, given a high level of
antiviral potency (EC 90 8-9 nM) and an extremely long t 1/2 in man of 60 h.
Treatment (200mg qd) led to a 2.1-log drop in viral load by day 20 in a Phase 2a
clinical trial, but this compound has not yet progressed further. 91 Compound
46 (ancriviroc, Sch-C) progressed into Phase 1 on the basis of good antiviral
activity and a strong oral PK profile (92% bioavailable, t 1/2 ¼ 10 h in dog). 32
The sterically encumbered amide bond resulted in restricted rotation around
both the N-CO bond (t 1/2 ¼ 5.6 h) and the CO-aryl bond (t 1/2 ¼ 23 h), giving
rise to an equilibrium mixture of four isomers. 92 Compound 47 (vicriviroc,
Sch-D) incorporates a symmetrical pyrimidine, which halves the number of
atropisomers. Relative to 46, vicriviroc is more potent and has less activity
against the hERG ion channel. It is currently in Phase 3 trials and shows an
impressive human PK profile (t 1/2 ¼ 28-33 h). 93 Takeda's first agent 48 (E921,
Tak-779) was a quaternary salt, which precluded oral delivery. Its development
as a subcutaneous agent was also terminated as a result of irritation around the
injection site. 94 However, the series was further developed, leading to the
identification of 49 (Tak-652). Clinical data show the compound to be well-
tolerated, with good bioavailability and low clearance (t 1/2 ¼ 9 h) following a 25
mg dose. 95 A second series yielded Takeda a third clinical candidate, 50 (Tak-
220), which shows good in vitro activity (EC 50 ¼ 0.6 nM) 96 and an encouraging
PK profile in monkey (bioavailability 29%, t 1/2 ¼ 6 h). 97 It is in Phase 1 trials
with Tobira Therapeutics.
9.16 Conclusions
A decade of research into CCR5 antagonists for HIV has delivered a diverse
array of chemotypes with a wide range of physicochemical properties. These
compounds span a range of compound classes, from quaternary salts to bases,
di-bases and zwitterions. All are high in molecular weight (496-700) and the
majority have a clog P 43. The need for potency has driven compound design
into this challenging region of chemical space; but, despite that, it has still been
possible to identify compounds worthy of progression. This success has
undoubtedly been supported by the development of robust and meaningful
assays that aid decision making and compound progression.
The ability to inhibit protein-protein interactions with small molecules is a
significant achievement. The success observed with CCR5 must be put into
context with the clinical failures seen when developing antagonists for other
chemokine receptors. 16,98 For example, CCR1 and CCR2 antagonists for
rheumatoid arthritis and multiple sclerosis have failed to show ecacy in Phase
2 trials (CP-481715, BX-471, MK-812). An antagonist (AMD3100) for CXCR4
was discontinued for HIV following leukocytosis, despite showing antiviral
ecacy. Notably, this agent has recently been approved as a tool to harvest
STEM cells. 99 The lack, or indeed unexpected ecacy, of these agents when