Selective 5-HT2Creceptor agonists: Design and synthesis of pyridazine-fused azepines

Article abstract of DOI:10.1016/j.bmcl.2016.06.060

Heterocycle-fused azepines are discussed as potent 5-HT_2Creceptor agonists with excellent selectivity over 5-HT_2Bagonism. Synthesis and structure activity relationships are outlined for a series of bicyclic pyridazino[3,4-d]azepines.

Full text of DOI:10.1016/j.bmcl.2016.06.060

Accepted Manuscript
Selective 5-HT2C receptor agonists: Design and synthesis of pyridazine-fused
azepines
Martin P. Green, Gordon McMurray, R. Ian Storer
PII:
S0960-894X(16)30671-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.06.060
BMCL 24013
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
1 June 2016
21 June 2016
23 June 2016
Please cite this article as: Green, M.P., McMurray, G., Ian Storer, R., Selective 5-HT2C receptor agonists: Design
and synthesis of pyridazine-fused azepines, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://
dx.doi.org/10.1016/j.bmcl.2016.06.060
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Martin P. Green, Gordon McMurray, and R. Ian Storer

Bioorganic & Medicinal Chemistry Letters
Selective 5-HT2C receptor agonists: design and synthesis of pyridazine-fused
azepines
Martin P. Greena, Gordon McMurrayb, R. Ian Storera,
aWorldwide Medicinal Chemistry, bDiscovery Biology, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Heterocycle-fused azepines are discussed as potent 5-HT2C receptor agonists with excellent
selectivity over 5-HT2B agonism. Synthesis and structure activity relationships are outlined for a
series of bicyclic pyridazino[3,4-d]azepines. By comparison with earlier published work, in vitro
assays predict a high probability for achieving CNS penetration for a potent and selective
compound 15a, a pre-requisite to achieve in vivo efficacy.
2009 Elsevier Ltd. All rights reserved.
Keywords:
5-HT2C receptor agonists
CNS penetration
Obesity
Pyridazino[3,4-d]azepines
Urinary incontinence
Serotonin (5-hydroxytryptamine, 5-HT 1) acts as an
agonist of at least 14 different receptors classified into
seven major families, 5-HT1-7. The 5-HT2 class of GPCR
receptors comprises three members 5-HT2A, 5-HT2B and 5-
HT2C. Studies have identified agonism of 5-HT2C in the
CNS to have potential for the treatment of a number of
conditions including obesity, urinary incontinence,
psychiatric disorders and sexual dysfunction.1-3
Figure 1. Serotonin and selected 5-HT2C clinical agonists.
However, in order to develop safe treatments, it has
been established that selectivity over agonism of the
structurally related receptors 5-HT2A and 5-HT2B is of
Pfizer has previously disclosed several 5-HT2C receptor
agonist templates.19-31 In particular, a variety of aromatic
heterocyclic piperazines have been reported to be potent
and selective 5-HT2C agonists. However, these series
proved challenging, requiring high lipophilicity to deliver
sufficient potency leading to suboptimal drug properties. In
addition, a number of advanced compounds showed
unacceptable levels of toxicity including mutagenicity in
the Ames test. Subsequent mechanistic studies proposed
bioactivation of the piperazine ring, a key part of the
pharmacophore, to be the likely cause of this toxicity.25 In
order to eliminate this inherent mutagenicity, it was
hypothesised based on molecular overlays that the
piperazine could be replaced with an aromatic-fused
paramount
importance.
Previously,
unselective
serotonergic agonists have been linked to adverse events in
humans. These include acute effects such as hallucinations
and cardiovascular events due to 5-HT2A agonism.4-7
However, arguably the greater concern, is chronic 5-HT2B
agonism which has been established to lead to irreversible
heart defects and pulmonary hypertension.8-9 Notably the
unselective anti-obesity treatment Fen-Phen was
withdrawn from the market in 1997 for causing irreversible
valvulopathy in a significant proportion of patients due to
5-HT2B agonism.
The search for potent and selective 5-HT2C agonists
identified vabicaserin (2) (SCA-136; Pfizer, formerly
Wyeth)10 as a potential therapy for schizophrenia and
lorcaserin (3) (APD-356; Arena) which gained limited
approval in 2012 as Belviq® for treatment of obesity
(Figure 1).11-12 Furthermore, several other small molecule
5-HT2C agonists have also been reported to be in early
clinical development or preclinical optimisation.13-18
azepine ring (Figure 2). Despite benzazepines
being
32
established as 5-HT2C agonists,27,
introducing a
heterocyclic core in order to minimise the lipophilicity was
desired as it was anticipated that this would lead to
improved ADME and safety properties.

potentially scalable synthetic route available. As a result, a
variety of azepine-fused azines and azoles were
synthesized (Table 1). Pharmacology was tested in an
established FLIPR functional agonism assay system
measuring the ability to induce a fluorescent based calcium
mobilization in recombinant CHO-K1 cells expressing the
human 5-HT2C receptor.21 Selected compounds were also
tested for their ability to inhibit binding of [3H]-
meselurgine at the human 5-HT2C receptor utilizing SPA
technology and cellular membrane preparations generated
from recombinant Swiss 3T3 cells.21 The selectivity of
compounds for 5-HT2C over 5-HT2B was also determined
using an analogous FLIPR assay for 5-HT2B functional
agonism (Table 1).21
Figure 2. Design of heterocycle-fused azepines.
To explore this hypothesis in the absence of structure-
based data necessitated building SAR for various fused
heterocyclic systems. A range of fused heterocycles were
explored. In the first instance these were limited to those
where there was a suitable, synthetically enabled and
Table 1. Primary pharmacology, selectivity, physicochemistry and in vitro ADME for fused-heterocycle azepines.
5-HT2C
5-HT2B
MDCK-
MDR1 ER
(BA/AB)
HLM Clint
(mL min-1 mg-1)
RRCK
(x10-6 cm/s)
b
b
Compound
logD
0.1
EC50
Kib
EC50
a
a
Emax
Emax
(M)
(M)
(M)
33-
6
7
8
0.19
75%
79%
90%
0.18
0.01
0.11
-
<8
<7
<8
20
13
1.1
1.0
3.0
50%
0.3
0.03
0.07
0.36
-
48%
24%
-0.1
NT
9
0.2
>10
>10
0%
0%
NT
-
-
13%
0%
<7
<8
14
2
1.0
1.3
10
-0.3
>10
11
-0.1
>10
0%
NT
-
0%
<7
<1
1.2
12
13
-0.5
0.1
>10
0%
57
NT
-
-
0%
3%
13
<7
<1
13
NT
1.0
4.98
2.70
a % activation at 10 M.; bMean of at least two replicates; NT denotes not tested; “-“ denotes no defined EC50 curve obtained
From this initial study, it was concluded that the fused
diazine systems 6-13 provided the better opportunities
based on both agonist potency and lipophilic efficiency. As
and low levels of efflux in Madin-Darby Canine Kidney
(MDCK) cells transfected with the MDR-1 gene encoding
the P-glycoprotein (P-gp) efflux transporter, suggested
these templates should also be readily CNS penetrant and
therefore ideal for further optimization.35
As previously disclosed, optimization of the
pyrimidine-fused template led to the discovery that 4-
methylamino substitution 14 could offer enhancement to 5-
HT2C agonist potency and simultaneously offer beneficial
improvements of selectivity over 5-HT2B agonism.30
a
result, further work was initiated, focusing on
optimization of potency and selectivity over 5-HT2B for
both pyrimidine-fused 619,
and pyridazinone-fused 720
33
templates. In addition, data generated in a Ralph Russ
Canine Kidney (RRCK) cell line highlighted that these
compounds should exhibit good levels of passive
membrane permeability.34 Furthermore, good permeability

However, these structural changes also led to amino-
substituted compounds becoming substrates for P-
glycoprotein (P-gp) as shown by a large efflux ratio in the
MDCK-MDR1 assay (Figure 3). As P-gp is highly
expressed on the blood brain barrier it was anticipated that
this would increase the risk that such compounds would
display prohibitive levels of CNS restriction, thereby not
accessing the desired site of action in vivo for effective
modulation of 5-HT2C.35-38 This risk was confirmed by in
vivo dog pharmacokinetic and pharmacology studies with
compound 14. The use of a clinically correlated dog peak
urethral pressure (PUP) urology model of stress urinary
incontinence (SUI) showed limited efficacy when treated
with compound 14 relative to freely brain penetrant
polarity to promote both good levels of 5-HT2C agonist
potency and selectivity over 5-HT2B (Figure 5).
Figure 5. Design hypotheses for pyridazine-fused azepines.
These specific pyridazine-fused azepines had not
previously been synthesized as part of the original
heterocycle study (Table 1) due to lack of synthetic
precedent. However, as a specific design rationale for their
synthesis now existed, suitable chemistry was sought to
access the substituted pyridazine-azepine core.
30
analogue 6 (PF-03246799) from the same template.19,
Analysis of cerebral spinal fluid (CSF) samples from the
study animals implied low levels of CNS exposure even at
high blood plasma concentrations. Additionally, this model
allowed for a projection in regard to therapeutically
meaningful 5-HT2C EC50 and Emax values, specifically a
targeted profile of <200 nM and >30%, was deemed
adequate with the assay utilised. Such an in vitro
pharmacology profile for 5-HT2C was also thought to be
adequate for other relevant clinical indications
(unpublished pre-clinical in vivo observations).
Considering the fused pyridazines 15a-i it was
anticipated that the synthesis of such poly-substituted
pyridazines can present a challenge. However, it was
recognized that pyridazinone intermediate 21, which had
previously been used in the synthesis of compound 7,
could potentially provide a convenient bulk precursor for
the current synthesis, offering the option of a late-stage
introduction of the benzylic group. As a result, this
intermediate was intercepted to synthesise fused
pyridazines 15a-i in 3 steps (Scheme 1). This method
proceeded smoothly via formation of the corresponding
triflate 22, followed by sp2-sp3 Negishi coupling with
various benzyl zincates then Boc deprotection to yield the
desired products 15a-i.20 In terms of access to the key
intermediate 21, this could be synthesised either from the
commercially available methoxy compound 20 or
synthesised on scale from 1,3-ketoester 16 by alkylation
with ethyl bromoacetate to form diester 17, followed by
hydrolysis and decarboxylation to 1,4-keto-ester 18.
Subsequent treatment of the keto-ester 18 with
hydrazine, followed by oxidation with bromine formed
pyridazinone 19.
Me
HN
N
N
NH
NH
N
N
6
14
5-HT2C EC50 190 nM, Emax 75%
5-HT2B 33-50% @ 10 M
MDCK-MDR1 efflux ratio 1.2
5-HT2C EC50 39 nM, Emax 40%
5-HT2B EC50 >10 M, Emax <10%
MDCK-MDR1 efflux ratio 10
low CNS exposure in vivo
good CNS exposure in vivo
Figure 3. Aminopyrimidines show good selectivity but poor CNS exposure.
In an effort to retain the excellent 5-HT2C potency and
selectivity of compound 14 but with improved CNS
penetration, compound designs were sought to provide
reduced propensity for P-gp efflux. Literature
pharmacophore models for P-gp have highlighted
hydrogen bond Acc-Acc distances of ~2.5 Å and ~4.6 Å as
P-gp recognition features. As shown in Figure 4,
compound 14 modelling Acc-Acc distances of 2.4 Å, 4.1 Å
and 4.6 Å indicated close similarity to this P-gp
pharmacophore pattern of hydrogen bonding (Figure 4).39
Figure 4. Distances between hydrogen bond acceptors on compound 14.
Modelled using Macromodel® with OPLS-2005 force field in conjunction
with GB/SA solvation model.
This suggested that N-1 in combination with a 4-amino
substituent could be instrumental to P-gp recognition. To
test this hypothesis, it was proposed that pyridazine-fused
azepines 15 would offer suitable CNS permeable profiles
without P-gp efflux liability whilst maintaining ring
Scheme 1. General synthesis of pyridazines 15a-i. Reagents: (a) NaOEt, ethyl
bromoacetate; (b) (i) HCl reflux; (ii) ethylchloroformate, K2CO3; (c)
NH2NH2, EtOH; (d) Br2, CHCl3 (19% yield over 4-steps); (e) POCl3; (f)
NaOMe, MeOH; (g) KOH, MeOH; (h) HBr, AcOH; (i) Boc2O, TEA, CH2Cl2
(48% yield over 5-steps); (j) Tf2O, 2,6-lutidine, CH2Cl2, 23 °C, 2 h (83%
yield); (k) requisite zincate (RBnZnBr), Pd(PPh3)4, THF, rt for 15 mins then
60 °C for 3 h; (l) TFA, CH2Cl2, 23 °C, 2 h.

was no evidence of efflux by the P-glycoprotein (P-gp)
transporter as measured in the MDCK-MDR1 cell-line
(ER=1.0), in accordance with the original hypothesis.
Additionally, compound 15a caused no appreciable
agonism of the 5-HT2B receptor up to 10 M.
Parent pyridazinone 15a (EC50 130 nM, Emax 69%, logD 0)
proved to be a relatively potent and efficient 5-HT2C lead,
comparable to previous lead compound 6 (PF-03246799,
EC50 190 nM, Emax 75%, logD 0.1) which had shown
excellent in vivo efficacy (Table 2).19, 30 Importantly, there
Table 2. Primary pharmacology, selectivity, physicochemistry and in vitro ADME for pyridazine-azepines.
5-HT2C
5-HT2B
EC50
(M) (M)
MDCK-
MDR1 ER
(BA/AB)
HLM Clint
RRCK
Cmpd
R
R1
R2
logD
EC50
(M)
0.13
Ki
(Lmin-1 mg-1)
(x10-6 cm/s)
a
a
Emax
Emax
15a
15b
15c
15d
15e
15f
H
p-Cl
o-Cl
m-CF3
o-OMe
p-F
H
H
H
H
H
H
H
H
H
H
H
H
H
0.0
0.8
0.7
0.9
0.1
0.2
0.4
69%
32%
71%
37%
14%
16%
63%
0.08
0.12
0.20
0.25
0.55
0.45
0.20
-
0.41
0.80
0.45
-
29%
63%
41%
57%
40%
64%
36%
<7
<7
<7
<7
9
14
13
15
13
16
14
13
1.0
1.3
1.1
1.7
1.9
1.2
1.8
0.31
0.31
0.75
>10
>10
0.19
-
<7
<8
15g
H
Me
ent1
Me
ent2
H
-
15h
H
H
0.4
0.11
75%
0.17
-
55%
<8
14
14
1.6
1.9
15i
H
Me
NT
0.22
80%
0.52
NT
NT
<8
a % activation at 10 M.; bMean of at least two replicates; NT denotes not tested; “-“ denotes no defined EC50 curve obtained
However, attempts to improve the potency within this
series by varying the ring and benzylic substituents (Table
2, compounds 15b-h) plus addition of a 4-Me substituent
(15i) were all unsuccessful. Furthermore, addition of
lipophilic groups (compounds 15b-15d), resulted in
Author Information
Corresponding Author:
Tel: +44 (0)1304 641854; E-mail: ian.storer@pfizer.com
Abbreviations
erosion of functional selectivity over 5-HT2B. At this time,
30-31
by analogy with other related templates,20,
it was
ADME, absorption, distribution, metabolism, and
excretion; CHO, Chinese hamster ovary; CNS, central
nervous system; ER, efflux ratio; FLIPR, fluorescence
imaging plate reader; HLM, human liver microsomes;
MDCK, Madin-Darby canine kidney cell line; MDR-1,
multidrug resistance gene 1; P-gp, P-glycoprotein
transporter; RRCK, Ralph Russ canine kidney cell line;
SPA, scintillation proximity assay; TFA, trifluoroacetic
acid.
recognised that most potency and efficiency gains had been
obtained by changes building off the two positions
currently blocked by the pyridazine ring nitrogens. As a
result, further optimisation of this template was not
continued.
In summary, the rational design of a novel series of
heterocyclic pyridazine-fused azepines with potent 5-HT2C
agonist activity and low P-gp efflux ratios has been
described. This work delivered lead compound 15a via the
novel application of a late stage Negishi sp2-sp3 coupling
of a pyridazine-2-triflate 22 with various benzyl zincates
for exploration of optimal benzyl substitution.
References and Notes
1. Wacker, D. A.; Miller, K. J. Curr. Opin. Drug Discovery Dev. 2008, 11,
438.
2. Smith, B. M.; Thomsen, W. J.; Grottick, A. J. Expert Opin. Invest. Drugs
2006, 15, 257.
Acknowledgements
3. Rosenzweig-Lipson, S.; Dunlop, J.; Marquis, K. L. Drug News Perspect.
2007, 20, 565.
4. Kaumann, A. J.; Levy, F. O. Pharmacol. Ther. 2006, 111, 674.
5. Vollenweider, F. X.; Vollenweider-Scherpenhuyzen, M. F. I.; Babler, A.;
Vogel, H.; Hell, D. NeuroReport 1998, 9, 3897.
We
thank
the
Primary
Pharmacology
and
Pharmacokinetics, Dynamics and Metabolism groups for
provision of in vitro screening data. Also we thank William
McCarte for synthesis support.
6. Nichols, D. E. Pharmacol. Ther. 2004, 101, 131.
7. Villalon, C. M.; Centurion, D. N-S Arch. Pharmacol. 2007, 376, 45.
8. Abenhaim, L.; Moride, Y.; Brenot, F.; Rich, S.; Benichou, J.; Kurz, X.;
Higenbottam, T.; Oakley, C.; Wouters, E. N. Engl. J. Med. 1996, 335, 609.
9. Roth, B. L. N. Engl. J. Med. 2007, 356, 6.
10. Ramamoorthy, P. S.; Beyer, C.; Brennan, J.; Dunlop, J.; Gove, S.; Grauer,
S.; Harrison, B. L.; Lin, Q.; Malberg, J.; Marquis, K.; Mazandarani, H.;
Supplementary data
Supplementary data is available: experimental procedures
for the synthesis of compound 15a. This material is
available free of charge via the Internet.

Piesla, M.; Pulicicchio, C.; Rosenzwieg-Lipson, S.; Sabb, A.-M.; Schechter,
L.; Stack, G.; Zhang, J. Abstracts of Papers, 231st ACS National Meeting,
Atlanta, GA, United States, March 26-30, 2006, MEDI.
11. Fleming, J. W.; McClendon, K. S.; Riche, D. M. Ann. Pharmacother.
2013, 47, 1007.
12. Smith, B. M.; Smith, J. M.; Tsai, J. H.; Schultz, J. A.; Gilson, C. A.;
Estrada, S. A.; Chen, R. R.; Park, D. M.; Prieto, E. B.; Gallardo, C. S.;
Sengupta, D.; Dosa, P. I.; Covel, J. A.; Ren, A.; Webb, R. R.; Beeley, N. R.
A.; Martin, M.; Morgan, M.; Espitia, S.; Saldana, H. R.; Bjenning, C.;
Whelan, K. T.; Grottick, A. J.; Menzaghi, F.; Thomsen, W. J. J. Med. Chem.
2008, 51, 305.
S.; Coelho, R. V., Jr.; Soliman, V. F.; Schildknegt, K. Drug Metab. Dispos.
2007, 35, 848.
26. Kalgutkar, A. S.; Bauman, J. N.; McClure, K. F.; Aubrecht, J.; Cortina, S.
R.; Paralkar, J. Bioorg. Med. Chem. Lett. 2009, 19, 1559.
27. Fish, P. V.; Brown, A. D.; Evrard, E.; Roberts, L. R. Bioorg. Med. Chem.
Lett. 2009, 19, 1871.
28. Liu, K. K. C.; Lefker, B. A.; Dombroski, M. A.; Chiang, P.; Cornelius, P.;
Patterson, T. A.; Zeng, Y.; Santucci, S.; Tomlinson, E.; Gibbons, C. P.;
Marala, R.; Brown, J. A.; Kong, J. X.; Lee, E.; Werner, W.; Wenzel, Z.;
Giragossian, C.; Chen, H.; Coffey, S. B. Bioorg. Med. Chem. Lett. 2010, 20,
2365.
13. Monck, N. J. T.; Kennett, G. A. Prog. Med. Chem. 2008, 46, 281.
14. Stahl, S. M.; Lee-Zimmerman, C.; Cartwright, S.; Morrissette, D. A.
Curr. Drug Targets 2013, 14, 578.
15. Yang, H. Y.; Tae, J.; Seo, Y. W.; Kim, Y. J.; Im, H. Y.; Choi, G. D.; Cho,
H.; Park, W.-K.; Kwon, O. S.; Cho, Y. S.; Ko, M.; Jang, H.; Lee, J.; Choi, K.;
Kim, C.-H.; Lee, J.; Pae, A. N. Eur. J. Med. Chem. 2013, 63, 558.
16. Rosenzweig-Lipson, S.; Comery, T. A.; Marquis, K. L.; Gross, J.;
Dunlop, J. Handb. Exp. Pharmacol. 2012, 213, 147.
17. Sargent, B. J.; Henderson, A. J. Curr. Opin. Pharmacol. 2011, 11, 52.
18. Ahmad, S.; Ngu, K.; Miller, K. J.; Wu, G.; Hung, C.-p.; Malmstrom, S.;
Zhang, G.; O'Tanyi, E.; Keim, W. J.; Cullen, M. J.; Rohrbach, K. W.;
Thomas, M.; Ung, T.; Qu, Q.; Gan, J.; Narayanan, R.; Pelleymounter, M. A.;
Robl, J. A. Bioorg. Med. Chem. Lett. 2010, 20, 1128.
19. Andrews, M. D.; Fish, P. V.; Blagg, J.; Brabham, T. K.; Brennan, P. E.;
Bridgeland, A.; Brown, A. D.; Bungay, P. J.; Conlon, K. M.; Edmunds, N. J.;
af Forselles, K.; Gibbons, C. P.; Green, M. P.; Hanton, G.; Holbrook, M.;
Jessiman, A. S.; McIntosh, K.; McMurray, G.; Nichols, C. L.; Root, J. A.;
Storer, R. I.; Sutton, M. R.; Ward, R. V.; Westbrook, D.; Whitlock, G. A.
Bioorg. Med. Chem. Lett. 2011, 21, 2715.
29. Liu, K. K. C.; Cornelius, P.; Patterson, T. A.; Zeng, Y.; Santucci, S.;
Tomlinson, E.; Gibbons, C.; Maurer, T. S.; Marala, R.; Brown, J.; Kong, J.
X.; Lee, E.; Werner, W.; Wenzel, Z.; Vage, C. Bioorg. Med. Chem. Lett.
2010, 20, 266.
30. Storer, R. I.; Brennan, P. E.; Brown, A. D.; Bungay, P. J.; Conlon, K. M.;
Corbett, M. S.; DePianta, R. P.; Fish, P. V.; Heifetz, A.; Ho, D. K. H.;
Jessiman, A. S.; McMurray, G.; de Oliveira, C. A. F.; Roberts, L. R.; Root, J.
A.; Shanmugasundaram, V.; Shapiro, M. J.; Sherten, M.; Westbrook, D.;
Wheeler, S.; Whitlock, G. A.; Wright, J. J. Med. Chem. 2014, 57, 5258.
31. Rouquet, G.; Moore, D. E.; Spain, M.; Allwood, D. M.; Battilocchio, C.;
Blakemore, D. C.; Fish, P. V.; Jenkinson, S.; Jessiman, A. S.; Ley, S. V.;
McMurray, G.; Storer, R. I. ACS Med. Chem. Lett. 2015, 6, 329.
32. Thomsen, W. J.; Grottick, A. J.; Menzaghi, F.; Reyes-Saldana, H.;
Espitia, S.; Yuskin, D.; Whelan, K.; Martin, M.; Morgan, M.; Chen, W.; Al-
Shamma, H.; Smith, B.; Chalmers, D.; Behan, D. J. Pharmacol. Exp. Ther.
2008, 325, 577.
33. Compound 6 (PF-03246799) is commercially available via Sigma Aldrich
(catalog # PZ0229).
34. Di, L.; Whitney-Pickett, C.; Umland, J. P.; Zhang, H.; Zhang, X.;
Gebhard, D. F.; Lai, Y.; Federico, J. J.; Davidson, R. E.; Smith, R.; Reyner,
E. L.; Lee, C.; Feng, B.; Rotter, C.; Varma, M. V.; Kempshall, S.; Fenner, K.;
El-kattan, A. F.; Liston, T. E.; Troutman, M. D. J. Pharm. Sci. 2011, 100,
4974.
20. Brennan, P. E.; Whitlock, G. A.; Ho, D. K. H.; Conlon, K.; McMurray, G.
Bioorg. Med. Chem. Lett. 2009, 19, 4999.
21. Andrews, M. D.; Blagg, J.; Brennan, P. E.; Fish, P. V.; Roberts, L. R.;
Storer, R. I.; Whitlock, G. A. WO2008117169, 2008.
22. Allerton, C. M. N.; Andrews, M. D.; Blagg, J.; Ellis, D.; Evrard, E.;
Green, M. P.; Liu, K. K. C.; McMurray, G.; Ralph, M.; Sanderson, V.; Ward,
R.; Watson, L. Bioorg. Med. Chem. Lett. 2009, 19, 5791.
23. Andrews, M. D.; Green, M. P.; Allerton, C. M. N.; Batchelor, D. V.;
Blagg, J.; Brown, A. D.; Gordon, D. W.; McMurray, G.; Millns, D. J.;
Nichols, C. L.; Watson, L. Bioorg. Med. Chem. Lett. 2009, 19, 5346.
24. Siuciak, J. A.; Chapin, D. S.; McCarthy, S. A.; Guanowsky, V.; Brown,
J.; Chiang, P.; Marala, R.; Patterson, T.; Seymour, P. A.; Swick, A.; Iredale,
P. A. Neuropharmacology 2007, 52, 279.
35. Feng, B.; Mills, J. B.; Davidson, R. E.; Mireles, R. J.; Janiszewski, J. S.;
Troutman, M. D.; de Morais, S. M. Drug Metab. Dispos. 2008, 36, 268.
36. Schinkel, A. H. Adv. Drug Delivery Rev. 1999, 36, 179.
37. Begley, D. J. Curr. Pharm. Des. 2004, 10, 1295.
38. Doan, K. M. M.; Humphreys, J. E.; Webster, L. O.; Wring, S. A.;
Shampine, L. J.; Serabjit-Singh, C. J.; Adkison, K. K.; Polli, J. W. J.
Pharmacol. Exp. Ther. 2002, 303, 1029.
39. Penzotti, J. E.; Lamb, M. L.; Evensen, E.; Grootenhuis, P. D. J. J. Med.
Chem. 2002, 45, 1737.
25. Kalgutkar, A. S.; Dalvie, D. K.; Aubrecht, J.; Smith, E. B.; Coffing, S. L.;
Cheung, J. R.; Vage, C.; Lame, M. E.; Chiang, P.; McClure, K. F.; Maurer, T.