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 205

heterocyclic amine
containing templates

O

various
substituents

R

R

N N

N R

R

amide right hand side;
heterocycle or amide

target structures
central amine pKa 6-9
MWt. <500

phenyl containing
left hand side

Figure 9.6 Design strategy for a novel series of CCR5 antagonists.

Table 9.9 In vitro profiles of two piperidine leads showing antiviral ecacies

but high lipophilicities, resulting in little metabolic stability

O

N

O

N

N

N

N

O

O N

Compound 40 41

Fusion IC 50
(nM)

1 3

log D 2.6 3.5

HLM t 1/2 (min) 4 4

AV IC 90 (nM) 2 40

Binding IC 50
(nM)

8 nd

hERG IC 50
(nM)

9800 3410

Caco AB/BA 23/26 nd

give some rigidity. After two iterations, two lead series were identified, repre-
sented by compounds 40 and 41 (Table 9.9). Both compounds showed poor
metabolic stability in hepatic microsomes, presumably via a facile benzylic oxi-
dation. Further evolution of this series has not been reported.

9.15 Other CCR5 Antagonists
A number of other companies have invested significant work to identify CCR5
antagonists for HIV and for other indications, such as transplant rejection. 87