Part 1: N-Alkylated glycines as potent α2δ ligands

Article abstract of DOI:10.1016/j.bmcl.2011.04.045

A new series of glycine-derived ligands of the α₂δ subunit of voltage gated calcium channels is described. Several novel compounds (7) based on (6) were prepared that possessed a potency <100 nM in the α₂δ binding assay.

Full text of DOI:10.1016/j.bmcl.2011.04.045

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3764–3766
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Part 1: N-Alkylated glycines as potent
a2d ligands
Lisa R. Thompson a, , David C. Blakemore a, Delphine Brugier a, Justin S. Bryans a, , Wai-Lam A. Chu b,
⇑
Graham N. Maw a, Cedric Poinsard a,à, David J. Rawson a, Andrew N. Warren a
a Sandwich Laboratories, Pfizer Global Research and Development, Sandwich, Kent, CT13 9NJ, UK
b Pfizer Global Research and Development, 10777 Science Center Drive, San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 30 April 2011
A new series of glycine-derived ligands of the a2d subunit of voltage gated calcium channels is described.
Several novel compounds (7) based on (6) were prepared that possessed a potency <100 nM in the a2d
binding assay.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
a2d
Gabapentin
N-Alkylated glycine
Amino acid
Gabapentin (NeurontinÒ) (1)1 and its successor, Pregabalin
(Lyrica) (2), are anticonvulsant drugs that have been approved
for the treatment of epilepsy and various neuropathic pain states.2
Pregabalin has superior potency and pharmacokinetics,3 and has
been accepted for the treatment of anxiety disorders,4 diabetic
peripheral neuropathy5 and post-herpetic neuralgia.2 It was the
first FDA approved medication for the treatment of fibromyalgia
in the US in 2007.6 Gabapentin (1) and Pregabalin (2) exert their
activity by regulating the release of several excitatory neurotrans-
investigated the effects of aromatic substitution (R1) and hetero-
atom linker (X) (Table 1).
For the thioether analogues (X = S) increasing lipophilicity im-
proved a2d binding affinity (11 > 10 > 9 > 8 > 6) whilst introduction
of polarity was detrimental to potency (15 < 14 < 13 < 11). Para-
substitution on the phenyl ring was favoured over meta-substitu-
tion, 10 > 12.
To understand the significance of the sulfur atom on activity,
oxygen linked analogues were also synthesised and the effect of
conformational changes were explored through introduction of a
mitters by binding to the a2d protein subunit of the voltage-gated
calcium channel, with IC50 values of 140 and 80 nM, respectively.7
There have been several recent publications disclosing other po-
tent a
2d ligands: the substituted benzylhomocysteines (3),8 substi-
CO2H
NH2
CO2H
NH2
tuted gababutins (4)9,10 and the bicyclic gababutins (5) (Fig. 1).11
In our quest to find alternative amino acids with improved po-
tency and efficacy, we discovered a novel series of N-alkylated gly-
cine-derived compounds, exemplified by compound (6) (Fig. 2).
1
2
CO2H
NH2
NH2
CO2H
Compound (6) showed weak binding affinity to the
a2d subunit
S
(IC50 = 5.4 M) and the aim of the project was to optimise the pro-
l
CO2H
NH2
R
R
file by preparation of compounds of general formula (7) with a tar-
get binding potency of <100 nM and a preclinical pharmacokinetic
profile predicting human half-life greater than 6 h. This paper de-
scribes the exploration of SAR of the N-alkylated glycine deriva-
3
5
4
Figure 1. Structure of Gabapentin (1), Pregabalin (2), substituted benzyl-homocy-
steines (3), substituted gababutins (4) and bicyclic gababutins (5).
tives and optimisation of
a2d potency. Our initial efforts
S
O
O
X
R1
N
H
N
H
R2
OH
⇑
OH
Corresponding author. Tel.: +44 01304 648733, fax: +44 01304 651817.
E-mail address: david.rawson@pfizer.com (D.J. Rawson).
Present address: Drug Discovery Group, MRC Technology, 1-3 Burtonhole Lane,
Mill Hill, London, NW7 1AD, UK.
X = S, O, CH2
7
6
R1 = mono substituted aryls, fused het
2 = H, alkyl, racemic or chiral
R
à
Present address: Galderma, Sophia Antipolis, 2400 Route des Colles, 06902 BIOT,
France.
Figure 2. The lead compound (6) and its analogues (7).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.04.045

L. R. Thompson et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3764–3766
3765
Table 1
O
O
a
2d Binding affinity of compound 6–21
b
a
S
O
O
O
N
H
O
NH
N
O
X
OBut
R1
N
H
OBut
R
R2
OH
R2
22
23
24
Compd
6a
X
S
S
R1
a
2d IC50 (nM)12
c
H
H
5400
2500
S
O
OH
N
8a
H
F
R
.HCl
9a
S
S
H
H
195
59
25
Cl
Br
10a
Scheme 1. Reagents and conditions: (a) NaH (60% oil dispersion), THF, 0 °C, 30 min,
t-butyl bromoacetate, rt, 18 h, (97%); (b) thiophenol, t-BuOK in 2-methyl-2-
propanol, 60 °C, 30 min, (20), 80 °C, 5 h, (70–90%); (c) 4 M HCl in dioxan (86%).
Br
N
12b
S
S
H
H
428
83
SH
S
O
S
b
a
N
H
13b,c
NH2
OBut
R
R
R
14b
15b,d
16e
17f
S
H
680
900
NC
27
26
28
c
S
H
H2N
O
O
O
O
H
6590
523
S
O
N
H
Cl
Cl
Br
Br
OH
R
Me
.HCl
29
18g
19g
Me (S)
Me (R)
441
Scheme 2. Reagents and conditions: (a) (26), NaHCO3, 2-bromo-ethylamine
hydrobromide, absolute EtOH, 90 °C, 6 h, (44%); (b) t-butyl bromoacetate, Et3N,
DCM, rt, 18 h; (c) 4 M HCl in dioxan, rt.
6670
20e
21e
O
O
Et
Et
214
40
Br
Cl
a, b
c
O
O
HO
HO
OBut
N
NH2
N
R2 Boc OBut
R2
R2 Boc
O
a
b
c
Synthesised by Scheme 1.
Synthesised by Scheme 2.
R1
The thiol starting material was prepared from the corresponding triflate, by
30
31
32
converting the triflate into the triisopropylsilanethiolate, followed by removal of the
d
R2 = H
or Et
SiiPr3 with CsF.13
d
Compound 15 was prepared from the reduction of (28) when R = CN.
Synthesised by Scheme 3.
Synthesised by Scheme 4.
Synthesised by Scheme 5.
e
O
O
N
H
f
R2
OH
g
R1
33
Scheme 3. Reagents and conditions: (a) Et3N, Et2O, t-butyl bromoacetate, 0 °C, 3 h
to rt 18 h; (b) Boc2O, NaOAc, dioxan, rt, 4 h, (49% over 2 steps); (c) PPh3, substituted
phenol, DIAD, THF, 0 °C to rt, (60%); (d) TFA, DCM, Dowex, (38%).
chiral centre alpha to the heteroatom (Table 1). In general, the thi-
oether analogues were more potent than their oxygen counterparts
(e.g., 9 > 16). Some of this potency can be regained by adding a
small alkyl substituent next to the oxygen (e.g., 17 > 16). In the
oxygen series, the (S) stereochemistry was preferred over (R)
(18 > 19). When X = O, meta-substitution was more favourable
than para (21 > 20).
Two general synthetic routes used to prepare the sulfur ana-
logues shown in Table 1 which are depicted in Schemes 1 and 2.
In Scheme 1 and 2-oxazolidinone (22) was alkylated with t-butyl
bromoacetate to give the t-butyl ester (23). The carbamate (23)
underwent ring opening with a thiolate anion, followed by an
in situ decarboxylation to afford the glycine ester derivative
(21).14 Acidic deprotection gave the amino acid (25) as the hydro-
chloride salt.
The oxygen-linked compounds shown in Table 1, were prepared
by one of three routes (Schemes 3–5). Scheme 3 depicts the prep-
aration of a racemic final compound, starting with the b-amino
alcohol (30). The b-amino alcohol (30) was alkylated with t-butyl
bromoacetate, followed by N-Boc protection to give the alcohol
derivative (31). The alcohol (31) underwent Mitsunobu reaction
to afford the phenyl ether (32), followed by in situ acidic ester
hydrolysis and N-Boc deprotection to yield (33).
Scheme 4 depicts an alternative route to the racemic series,
reductive amination of the aldehyde (34),16 and subsequent ester
hydrolysis led to the racemic amino acid (36).
The chiral analogues (18 and 19) were prepared from the chiral
b-amino alcohol (37) (Scheme 5). Initially the nitrogen was pro-
tected as the Boc derivative,17 followed by Mitsunobu reaction
(38),18 alkylation (39) and acidic deprotection to afford the chiral
amino acids (37).
In Scheme 2 the thioethylamine (27) was prepared by alkylation
of the thiophenol compound (26).15 The resultant primary amine
(27) was alkylated with t-butyl bromoacetate to produce (28), fol-
lowed by deprotection with hydrochloric acid to yield the salt (29).

3766
L. R. Thompson et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3764–3766
O
b
O
O
O
O
a
O
N
H
N
H
H
OBut
OH
.HCl
R
R
R
35
36
34
Scheme 4. Reagents and conditions: (a) t-Butyl glycine ester, Et3N, anhydrous DCM, rt, 1 h: NaBH(OAc)3, rt, 48 h, (25%); (b) 4 M HCl, dioxan, (89%).
further.In Parts 2 and 3 of this series of papers we will detail how
constrained analogues have improved both the pharmacokinetic
profile and the a2d binding affinity of these leads.
O
O
a, b
Br
c, d
HO
O
N
H
NH2
*
NHBoc
*
*
OBut
Br
37
38
39
e
References and notes
1. Bryans, J. S.; Wustrow, D. J. Med. Res. Rev. 1999, 19, 149.
2. Chiechio, S.; Zammataro, M.; Caraci, F.; Rampello, L.; Copani, A.; Sabato, A. F.;
Nicoletti, F. Clin. Drug Invest. 2009, 29, 203.
O
O
N
*
H
OH
.HCl
3. Guay, D. R. P. J. Geriatr. Pharmacother. 2005, 3, 274.
Br
4. Tassone, D. M.; Boyce, E.; Guyer, J.; Nuzum, D. Clin. Ther. 2007, 29, 27.
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Meltzer, L. T.; Schwartz, J. B.; Taylor, C. P.; Thorpe, A. J.; Vartanian, M. G.; Wise,
L. D.; Zhi-Su, T.; Weber, M. L.; Wustrow, D. J. J. Med. Chem. 2005, 48, 2294.
8. Mortell, K. H.; Anderson, D. J.; Lynch, J. J., III; Nelson, S. L.; Sarris, K.; McDonald,
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Bioorg. Med. Chem. Lett. 2006, 16, 1138.
40
Scheme 5. Reagents and conditions: (a) Boc2O, CH2Cl2, 0 °C to rt, 3 h (67%); (b)
DEAD, PPh3, 4-bromophenol, THF, 0 °C to rt (40%); (c) 4 M HCl, dioxan, rt, 18 h
(84%); (d) Et3N, t-butyl bromoacetate, THF, 0 °C to rt, 18 h (60%); (e) 4 M HCl,
dioxan, rt, 18 h (87%).
In conclusion, lipophilic substituents at position R1 in the N-
9. Blakemore, D. C.; Bryans, J. S.; Carnell, P.; Field, M. J.; Kinsella, N.; Kinsora, J. K.;
Meltzer, L. T.; Osborne, S.; Thompson, L. R.; Williams, S. C. Bioorg. Med. Chem.
Lett. 2010, 20, 248.
alkylated glycine series are optimal for
a2d potency (naph-
10. Blakemore, D. C.; Bryans, J. S.; Carnell, P.; Chessum, N. E. A.; Field, M. J.;
Kinsella, N.; Kinsora, J. K.; Osborne, S. A.; Williams, S. C. Bioorg. Med. Chem. Lett.
2010, 20, 362.
11. Blakemore, D. C.; Bryans, J. S.; Carnell, P.; Carr, C. L.; Chessum, N. E. A.; Field, M.
J.; Kinsella, N.; Osborne, S. A.; Warren, A. N.; Williams, S. C. Bioorg. Med. Chem.
Lett. 2010, 20, 461.
thyl > Ph > Br > Cl > CN) and the achiral thioethers were more
potent than the achiral oxyethers. The preferred stereochemistry
at R1 is (S) when X = O.
The most potent compound discovered in this series (11) was
progressed to rat iv pharmacokinetic profiling (summarised
below):
12. The biological activity of the compounds was measured in
a radioligand
binding assay using [3H] gabapentin and the
a
2d subunit derived from porcine
tissue Gee, N. S.; Brown, J. P.; Dissanayake, V. U. K.; Offord, J.; Thurlow, R.;
Woodruff, G. N. J. Biol. Chem. 1996, 271, 5776.
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14. Ishibibashi, H.; Uegaki, M.; Sakai, M.; Takeda, Y. Tetrahedron 2001, 50, 2115.
15. Mascagna, D.; Constanti, C.; D’Ischia, M.; Prota, G. Tetrahedron 1994, 50, 8757.
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17. Moree, W. J.; Van der Marcel, G. A.; Liskamp, R. J. J. Org. Chem. 1995, 60, 5157.
18. Chorida, M. D.; Harman, W. D. J. Am. Chem. Soc. 2000, 122, 2725.
Vd (L/kg)
Clun (ml/min/kg)
23
t1/2 (h)
tmax (h)
0.6
1.1
0.25
Unfortunately based on this rat pharmacokinetic data the predicted
human half life is <5 h and the compounds were not progressed