6954
R. Skerlj et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6950–6954
compounds is similar to that of compounds 4 (Scheme 2). Although,
CO2H
CO2H
Br
CO2Et
Br
a,c,d
e, f
a-c
as exemplified by 3b the nitrile of 15 was first reduced to the pri-
mary amine which allowed installation of the amide followed by
introduction of the left hand side pyridine nitrile group.
Compound 4f was selected for further evaluation. The selectiv-
ity of 4f and related analogs was evaluated in Ca2+ flux assays
against a series of other closely related G-protein-coupled recep-
tors (GPCRs), which included CCR1, CCR2b, CCR4, CXCR1, CXCR2
and CXCR4, and were found to be non-inhibitory. In addition 4f
and analogs were not cross reactive to the M2 muscarinic receptor.
When tested against a panel of 5 isoforms of CYP 450 4f was found
Cl
N
9
NC
N
8
N
CO2H
g
F
N
H2N
N
F
N
11
10
O
h-k
l
CN
OH
N
H2N
BocHN
MeO
CN
14
13
12
to be non-inhibitory at concentrations >10 lM. Although 4f pro-
gressed to a 7-day safety study in rat and had an acceptable NOAEL
in parallel it was found to have an unacceptable cardiovascular
safety profile based on hERG inhibition, IC50 of 0.25 lM.
In conclusion a series of CCR5 antagonists were successfully
optimized to improve potency and achieve an acceptable in vitro
and in vivo profile but the series was not further progressed due
to cardiovascular safety concerns. In due course we will report
our efforts in mitigating the hERG liabilities.
m
N
H
N
n, o
N
N
N
NH2
MeO
CN
15
q, p, r
16
p
3b
4f
Scheme 2. Reagents and conditions: (a) m-CPBA, CH2Cl2; (b) POCl3, reflux, 44% for
two steps; (c) NaOH, EtOH, 90 °C, 88%; (d) TMSCN/Me2NCOCl, DMF, 80 °C, 82%; (e)
NaNO2, HBF4, 0 °C; (f) heptane, 90 °C, 36% for two steps; (g) t-BuLi, Et2O, À78 °C,
then CO2, À78 °C to rt, 73%; (h) MsCl, CH2Cl2, 76%; (i) NaCN, DMSO, 45 °C, 63%; (j)
CH3SO3H, CH3CN/EtOAc, 70 °C, 1 h; (k) NH4OH, 90% for two steps; (l) 1-ethylmeth-
yl-4-piperidone iodide, EtOH/H2O, 100 °C, 87%, >99% ee; (m) 4-methoxyaniline,
NaBH(OAc)3, CH2Cl2, 98%; (n) 4-methylnicotinoyl chloride, THF, Et3N, 87%; (o)
BH3ÁTHF, 65 °C, 90%; (p) HOBt, EDCI, DIPEA, 9, DMF, 63%; (q) Raney Ni, H2, MeOH,
62%; (r) 6-(bromomethyl)-picolinonitrile, DIPEA, KI, CH3CN, 80 °C, 42%.
References and notes
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