Oxadiazolone bioisosteres of pregabalin and gabapentin

Article abstract of DOI:10.1016/j.bmcl.2008.10.101

A series of oxadiazolone bioisosteres of pregabalin 1 and gabapentin 2 were prepared, and several were found to exhibit similar potency for the α₂-δ subunit of voltage-gated calcium channels. Oxadiazolone 9 derived from 2 achieved low brain upt

Full text of DOI:10.1016/j.bmcl.2008.10.101

Bioorganic & Medicinal Chemistry Letters 19 (2009) 247–250
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Oxadiazolone bioisosteres of pregabalin and gabapentin
David J. Wustrow a, Thomas R. Belliotti a, Thomas Capiris a, Clare O. Kneen b, Justin S. Bryans b, Mark J. Field b,
Dic Williams b, Ayman El-Kattan a, Lisa Buchholz a, Jack J. Kinsora a, Susan M. Lotarski a, Mark G. Vartanian a,
Charles P. Taylor a, Sean D. Donevan a, Andrew J. Thorpe c, Jacob B. Schwarz a,
*
a Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA
b Sandwich Laboratories, Sandwich, Kent, CT13 9NJ, UK
c St. Louis Laboratories, 700 Chesterfield Parkway W, Chesterfield, MO 63017, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of oxadiazolone bioisosteres of pregabalin 1 and gabapentin 2 were prepared, and several were
Received 15 August 2008
Revised 17 October 2008
Accepted 20 October 2008
Available online 25 October 2008
found to exhibit similar potency for the a2-d subunit of voltage-gated calcium channels. Oxadiazolone 9
derived from 2 achieved low brain uptake but was nevertheless active in models of osteoarthritis. The
high clearance associated with compound 9 was postulated to be a consequence of efflux by OAT and/
or OCT, and was attenuated on co-administration with cimetidine or probenecid.
Ó 2008 Published by Elsevier Ltd.
Keywords:
Oxadiazolone
Acid bioisostere
Pregabalin
Gabapentin
a2-d
Pregabalin 11 was approved in the U. S. and Europe as an add-on
The synthetic route used to access oxadiazolones from the corre-
sponding
-amino acids is shown in Scheme 1.10 N-protection and
therapy for epilepsy, and also for the treatment of neuropathic
pain.2 In June 2007 it became the first medication approved in
the U. S. for the treatment of fibromyalgia,3 and it has also been ap-
proved in the E. U. for the treatment of generalized anxiety disor-
der.4 The therapeutic efficacy of 1 has been linked to binding at the
c
amidation of cycloheptane 3 via the mixed anhydride was followed
by dehydration with cyanuric chloride11 to afford nitrile 4. Treat-
ment of the nitrile with hydroxylamine under alkaline conditions
furnished N-hydroxyamidine 5 as a ca. 1:1 mixture of E:Z isomers.
Cyclization was effected with CDI, and finally acidic deprotection
gave amino oxadiazolone 6.
a
2-d subunit of voltage-gated calcium channels.5 Recently, we re-
ported that the carboxylate functions of pregabalin 16 and gaba-
pentin 27 may be replaced by tetrazole, affording compounds
that demonstrated similar in vitro and in vivo pharmacology to
the parent amino acids. It was subsequently communicated that
this approach could be extended to replacement with an oxadiazo-
lone,8 which has previously been shown to be a viable replacement
for carboxylic acids.9 Herein we wish to disclose additional SAR
CO2H
NH2
CN
a,b,c
d
NHBoc
and biological data of
protein.
c
-amino oxadiazolones that target the a2-d
3
4
O
NH2
HN
OH
O
N
e,f
CO2H
N
CO2H
NH2
NHBoc
NH2
H
NH2
5
6
1
2
Scheme 1. Synthesis of oxadiazolone
6 from amino acid 3. Reagents and
conditions: (a) Boc2O, 1 N NaOH, THF; (b) i-BuOCOCl, Et3N, THF, then NH3; (c)
cyanuric chloride, DMF (65%, 3 steps); (d) NH2OH-HCl, KOH, EtOH (78%); (e) CDI,
THF (52%); (f) HCl; (g) dioxane (100%).
* Corresponding author. Tel.: +1 7346222580; fax: +1 7346225165.
E-mail address: jacob.schwarz@pfizer.com (J.B. Schwarz).
0960-894X/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2008.10.101

248
D. J. Wustrow et al. / Bioorg. Med. Chem. Lett. 19 (2009) 247–250
We had previously reported that the affinity of tetrazole deriv-
acid drugs such as pregabalin 116 and the tenfold lower brain levels
observed for 9 in comparison to 1 (Table 4). However, oxadiazolone
9 has been shown to reduce progression of cartilage damage in a
dog model of osteoarthritis.17,18 It has recently been suggested that
ative 7 was found to be comparable to that for 1 and 2, and that
elimination of the acidic function via alkylation as in 8 resulted
in complete reduction of potency for
a
2-d (Table 1).7 [1,2,4]Oxa-
diazolones 9 and 10 derived from 2 gave results consistent with
the tetrazoles, suggesting that this heterocycle was in fact a suit-
able carboxylic acid replacement for gabapentin.8 Importantly, nei-
ther the tetrazole 7 or oxadiazolone 9 were substrates for the
system L amino acid transporter, previously shown to facilitate en-
try of amino acids such as 1 and 2 into the brain.12
a2-d subunit ligands may influence the availability of calcium
channel complexes at the plasma membrane via an action in the
intracellular compartment, and that access to this compartment
is gained via the system L transporter.19 As compound 9 had low
affinity for system L, it suggests that either it does not require ac-
cess to this compartment, or that other transporters may permit
access. The significance of this for the actions of these ligands in
different animal models remains to be established.
The SAR of various oxadiazolone analogs is shown in Table 2.
Contraction of the carbocycle to the cyclopentane 11 resulted in
a marked loss of potency for
a
2-d relative to 2. However, expansion
Consistent with its hydrophilic physicochemical properties and
low molecular weight, compound 9 demonstrated only minimal
protein binding (Fu > 0.9). It was not significantly metabolized,
and once absorbed was excreted predominantly in the urine as un-
changed parent drug. In addition, unbound renal clearance of 9 was
significantly higher than the rat renal glomerular filtration rate of
5.2 mL/min/kg (Table 5). This suggested that compound 9 under-
went net renal secretion,20 possibly mediated by transporter(s) lo-
cated on the renal proximal tubules such as organic cation
transporter (OCT) and organic anionic transporter (OAT).
as in cycloheptane 6 resulted in enhanced affinity. Complete loss of
potency was observed on further expansion to cyclooctane 12. Pre-
sumably this was a consequence of the inability of the ring to sup-
port the axial positioning of the carboxylate required for
a2-d
activity.13 With respect to substitution about the carbocyclic ring
of 9, similar to our previous observations14 incorporation of a 3-
methyl group with the appropriate stereochemistry as in 13 rela-
tive to the amino acid bearing carbon resulted in increased affinity
for
a2-d. Incorporation of a second methyl group at the 5-position
as in 14 further enhanced potency for
a
2-d, although the diastereo-
When compound 9 was co-administered intravenously with
probenecid or cimetidine (known inhibitors for OAT and OCT
transporters, respectively), its clearance was reduced by 57% and
35% relative to control.21 This may suggest that OCT and OAT trans-
porters were playing a role in the renal excretion of compound 9
and thereby contributed to the observed renal clearance (Fig. 1).22
In summary, oxadiazolone replacements of pregabalin 1 and
gabapentin 2 were prepared and some displayed affinity for the
mer 15 was devoid of activity. The synthetic route used to access
the amino acid precursors to 14 and 15 have previously been re-
ported.13 Finally, the oxadiazolone analog 16 of pregabalin 1
showed reduced potency in comparison to the gabapentin oxa-
diazolone 9, a similar result to that obtained for the tetrazole
replacement.7
The oxadiazolone 9 was inactive in animal models where brain
penetration is a requirement. These include the DBA/2 audiogenic
seizure model and the water lick conflict test for anxiety
(Table 3).15 This profile is consistent with the reduced affinity of
9 for the system L transporter that facilitates brain uptake of amino
a2-d subunit. Unlike 1 and 2, however, oxadiazolone 9 was inactive
at the system L transporter which resulted in poor brain uptake. As
a result, in vivo activity was limited to models of osteoarthritis.
Finally, the high clearance associated with oxadiazolone 9 was
Table 1
Affinity of gabapentin carboxylate replacements for
a2-d and system L transporter (LST).
A
NH2
2-d binding IC50, nMa
LST binding IC50
(l
M)
b
Compound
A
a
1
Pregabalin
CO2H
80
70
158
30
2 (Gabapentin)
N
N
N
N
7
8
100
>10,000
N
H
N
O
N
>10,000
N
CH3
O
N
N
9 (PD 200347)
210
>10,000
N
H
O
O
10
>10,000
N
CH3
a
IC50 is the concentration (nM) producing half-maximal inhibition of the specific binding of [3H]gabapentin binding to pig brain membranes, see Ref. 5.
IC50 is the concentration (nM) producing half-maximal inhibition of the uptake of [3H]leucine into CHO cells, see Ref. 12.
b

D. J. Wustrow et al. / Bioorg. Med. Chem. Lett. 19 (2009) 247–250
249
Table 2
Table 4
SAR of carbocyclic portion of amino oxadiazolones.
Exposure of compounds 1 and 9 at 2 h post 30 mg/kg PO dosing in Sprague–Dawley
rats.
O
Compound System L IC50
M)
Brain levels (ng/
mL)
Plasma levels (ng/
mL)
B/P
HN
O
(l
1
9
158
>10,000
7360
750
25,643
15,000
0.29
0.05
N
NH2
a
Compound
Carbocycle
a2-d IC50 (nM)
Table 5
Rat pharmacokinetic parameters for compounds 1, 2, and 9.
9
11
6
Cyclohexyl
Cyclopentyl
Cycloheptyl
Cyclooctyl
210
1140
158
Parameter
Pregabalin 1
Gabapentin 2
PD 200347 9
Bioavailability (%F)
83
76
97
20.3
1.6
2.2
1.25
12
5600
Clearance (mL/min/kg)
Plasma half-life (t1/2) (h)
2.9
2.7
14.8
0.79
6.0
1.5
8.6
0.65
O
O
AUCa
(lg h/mL)
Vdssb (L/kg)
HN
a
Area under the concentration vs time curve.
Volume of distribution.
N
13
84
b
NH2
10000
O
O
PD-0200347 with cimetidine coadministration
PD-0200347 alone
PD-0200347 with probenecid coadministration
HN
HN
N
14b
70
1000
100
10
NH2
O
O
N
15b
>10,000
NH2
0
2
4
6
8
Time (hr)
Figure 1. Average plasma concentration vs. time profiles for Wistar rats treated
with PD 200347 alone (open circles, n = 7), and co-administered with probenecid
(closed triangles, n = 3) or cimetidine (closed circles, n = 3) after 3 mg/kg IV infusion
over 5 min.
O
HN
16b
1500
O
N
Acknowledgments
NH2
The authors are grateful to Nirmala Suman-Chauhan and Ti-Zhi
Su for their expertise in providing a2-d and system L binding data.
a
IC50 is the concentration (nM) producing half-maximal inhibition of the specific
binding of [3H]gabapentin binding to pig brain membranes, see Ref. 5.
b
Compound is racemic.
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