Bioorganic & Medicinal Chemistry Letters
Discovery of a novel series of cyclic urea as potent CCR5 antagonists
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Maosheng Duan , Wieslaw M. Kazmierski , Matt Tallant, Jung Ho Jun, Mark Edelstein, Rob Ferris,
Dan Todd, Pat Wheelan, Zhiping Xiong
Infectious Disease Medicine Discovery and Development, GlaxoSmithKline Five Moore Drive, Research Triangle Park, NC 27706, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of cyclic urea-based CCR5 antagonists was designed aiming to resolve instability issue in
the fasted simulated intestinal fluid (FSIF) associated with the acyclic urea moiety in 1. This class of CCR5
compounds demonstrated high antiviral activities against HIV-1 infection in both HOS and PBL assays.
Further evaluation of these compounds indicated that 16-R not only substantially enhanced its stability,
but also exhibited excellent pharmacokinetics properties.
Received 24 June 2011
Revised 5 August 2011
Accepted 24 August 2011
Available online 28 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cyclic urea
CCR5
Antagonist
Pharmacokinetics
HIV-1
Chemokine
Combating against HIV infection continues to be a challenge to
public healthcare. Highly active anti-retrovirals therapy (HAART)
has significantly increased the life expectancy of HIV patients
and reduced morbidity, however, mutant resistance and patient
compliance due to side effects have become serious issues. Discov-
ery and development of new anti-HIV medicines with novel mode
of action (MOA) promise to overcome these challenges. Since hu-
man chemokine receptor 5 (CCR5) was identified as one of viral en-
try co-receptors and plays an essential role in HIV viral
replication,1 efforts to discover human CCR5 antagonists as anti-
HIV agents have been extensively pursued in the pharmaceutical
industry,2 which ultimately led to several small molecules in clin-
ical development and one FDA approved drug (Maraviroc).3
We previously reported a series of acyclic urea as CCR5 antago-
nists, exemplified by 1.4 This series of compounds not only demon-
strated potent anti-HIV activity in both human osteosarcoma
(HOS) cell and peripheral blood lymphocytes (PBL) cell assays,
but also exhibited promising DMPK profiles. However, compound
1 was found to have limited stability in fasted simulated intestinal
fluid (FSIF) at pH 6.0 at 40 °C (t1/2 = 334 h). Further degradation
fragment analysis revealed that the acyclic urea portion of the mol-
ecule was responsible for its instability, and fragments A, B and C
were detected by LC–MS, Figure 1. Since the urea deprotonation
mechanistically precedes such a degradation, to rectify the issue,
we designed the molecules that ‘lack’ the acidic proton in the NH
moiety.
To that end, we first designed and synthesized carbamate 2,
which had IC50 = 29 nM in HOS cell assay against the Ba-L strain
of HIV-1. Despite some loss of potency compared to 1, carbamate
2 appeared to support our general strategy and that the acidic pro-
ton in the NH urea moiety was not a key pharmacophore. Mean-
while, we also prepared the benzyl-substituted urea 3 to probe
different chemical space. Surprisingly, 3 was highly potent against
HIV-1 infection with IC50s = 1.7 nM and 0.9 nM in both HOS and
PBL cell assays against the Ba-L strain of HIV-1,5 respectively.
Following these results, we rationalized that five/six-member
rings tying up both urea nitrogen atoms could be tolerated as phar-
macophores and would also substantially improve the urea stabil-
ity, Figure 2. To test this hypothesis, the imidazolidine-2, 4-dione
racemic analogue 4 was designed and synthesized, Scheme 1. Thus,
5-amino-2,4-difluorobenamide 5 was treated with 4-nitro-phenyl
chloroformate in the presence of N,N-dimethyl aniline to provide
carbamate 6, while the reductive alkylation of methyl
amino(phenyl)acetate and Boc protected piperidione yielded
amine 7. Subsequent reaction of 7 with carbamate 6 produced imi-
dazolidine-2, 4-dione 8 via spontaneous cyclization of transiently-
forming acyclic urea intermediate. After the Boc protecting group
was removed, the resulting piperidine 9 was reductively alkylated
with aldehyde 10 to furnish 4 as a racemic mixture. Rewardingly,
compound 4 had IC50 = 14 nM in HOS antiviral assay.
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Corresponding authors. Tel.: +1 86 21 51163719; fax: +1 86 21 51163766
We next pursued the synthesis of the cyclic urea 16, a partially
reduced analogue of the imidazolidine-2, 4-dione analogue. Since
the terminal sulfonamide moiety in 4 was found to be metaboli-
(M.D.); tel.: +1 919 483 6942; fax: +1 919 315 0430 (W.M.K.).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.