M. Packiarajan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5658–5662
5661
Table 4
Profiling data of selected key compounds (in vitro metabolic clearance, CYP inhibition and rat in vivo pharmacokinetic data24
)
Solc
(M)
hClint
rClint
CYP3A4
(IC50, M)
CYP2D6
(IC50, M)
hERG
(IC50, M)
Braine
(ng/g)
Plasmae
(ng/mL)
d
d
Compound
mGluR5 EC50
(nM)a
mGluR5 Ki
(nM)b
(L/min)
(mL/min)
6c
10.7
8.8
12.5
5.1
410
150
n/a
12
0.6
ND
2.7
1.0
22.0
ND
27.0
20.0
25
25
25
12
22
16
32
11
4
3
6
8
86
0
n/a
342
22
0
n/a
46
ent-6c (ꢀ)
3.1
2.7
3.1
12c
ent-12c (ꢀ)
230
ND = Not detectable.
n/a = Not available.
a
For the mGluR5 EC50 functional FLIPR assay see Table1, foot note (n >8).
For the mGluR5 binding assay was done using radiolabelled 3H–NAM ligand.
The solubility was measured from DMSO stock solution.22
b
c
The hClint and rClint are human (L/min) and rat (mL/min) intrinsic clearance, respectively and were determined according to Obach et al.,23 The rat and human maximum
d
liver blood flow corresponds to 20 mL/min and 1.5 L/min, respectively.
e
A single dose brain and plasma PK was assessed at 10 mg/kg ip in 2 animals at 1 h and averaged values are shown.24
analogs tethered with benzmorpholinone (19a), benzpiperazinone
(19b) and tetrahydroquinoline (19c) also resulted weaker NAMs
(IC50 = 550–800 nM). These data suggest a tight pharmacophore
for PAM efficacy.
References and notes
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Compounds 6c and 12c (Fig. 3) were separated using chiral
chromatography and both enantiomers were profiled. In both
cases, the (ꢀ) enantiomers of 6c (ent-6c (ꢀ)) and 12c (ent-12c
(ꢀ)) are more potent than the corresponding (+) enantiomers.
The ADME profiles of key compounds are depicted in Table 4.
The (ꢀ)-enantiomer of compound 6c exhibits potency comparable
to the racemic compound 6c. The compound ent-6c (ꢀ) could not
be detected upon microsomal incubation and the brain exposure
is below the detection limit. The (ꢀ)-enantiomer of compound
12c exhibits stronger potency (EC50 = 5.1 nM) than the racemic
12c analog at mGlu5 receptor with a binding affinity of 230 nM.
It does not have significant inhibition at any of the relevant cyto-
chrome P450 (CYP) isoforms (1A2, 2C9, 2C19, 2D6 and 3A4
IC50 > 11 lM). Plasma protein binding (PPB) data showed com-
pound ent-12c (ꢀ) was highly bound, with 99.7% and 99.3% bind-
ing in rat and human, respectively. In mdr-MDCK-1 permeability
study (Papp[A–B] = 20.0 cm/s ⁄ 10ꢀ6, Papp[A–B] = 6.4 cm/s ⁄ 10ꢀ6),25
the compound had no Pgp liability (B–A/A–B efflux ratio = 0.32).
The hERG IC50 of ent-12c (ꢀ) was determined to be 8
lM in the
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In summary, we have identified N-aryl pyrrolidinonyl oxadiaz-
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substitution at the N-aryl group is optimal for mGluR5 potency
while m-chloro and methyl substituents are optimal on the aryl
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identification of the potent compound ent-12c (ꢀ) with improve-
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We thank our colleagues Manual Cajina, Megan E. Nattini and
Kimloan Nguyen (Bioanalysis, pharmacokinetics metabolic stabil-
ity and CYP inhibition); Xu Zhang, Qing-Ping Han and Chi Zhang
(chiral separation and physicochemical); Michelle B. Uberti and
Christina L. Bonvicino (functional assay) for providing support to
this work.