Discovery of a series of potent, orally active α,α- disubstituted piperidine NK1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.08.059

Modification of prototype NK₁ antagonist 2 resulted in the synthesis of a series of simple amides 6 and retroamides 9. These compounds were shown to be potent and orally active NK₁ antagonists.

Full text of DOI:10.1016/j.bmcl.2010.08.059

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6313–6315
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of a series of potent, orally active
antagonists q
a,a-disubstituted piperidine NK1
a
a
a
a
a
Dong Xiao a, , Cheng Wang , Anandan Palani , Hon-Chung Tsui , Gregory Reichard , Sunil Paliwal ,
Neng-Yang Shih a, Robert Aslanian a, Ruth Duffy b, Jean Lachowicz b, Geoffrey Varty b, Cynthia Morgan b,
Fei Liu c, Amin Nomeir c
*
a Chemical Research Department, Merck Research Laboratories, Kenilworth, NJ 07033, USA
b CV & CNS Biology Department, Merck Research Laboratories, Kenilworth, NJ 07033, USA
c Drug Metabolism Department, Merck Research Laboratories, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Modification of prototype NK1 antagonist 2 resulted in the synthesis of a series of simple amides 6 and
retroamides 9. These compounds were shown to be potent and orally active NK1 antagonists.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 21 April 2010
Revised 11 August 2010
Accepted 12 August 2010
Available online 15 August 2010
Keywords:
NK1 antagonist
Dibasic amine metabolite
The neurokinin 1 (NK1) receptor belongs to the family of G-pro-
tein coupled receptors (GPCRs). This receptor mediates the action
of substance P and other tachykinins in both the central and
peripheral nervous systems. Therefore, the NK1 receptor antago-
nists may have therapeutic values in treating emesis, anxiety,
depression, inflammation, and pain.1–4 Recently, FDA approved
EmendÒ for the treatment of chemotherapy-induced nausea and
vomiting (CINV). This demonstrated the clinic utility of NK1 antag-
onists and several other compounds have undergone clinical trials
for a variety of medical indications.5
As part of the search for novel NK1 antagonists, we became inter-
ested in the 2,2-disubstituted piperidine 1 (Fig. 1).6 Our own work in
this area resulted in the discovery of a novel chemistry of metalla-
tion of N-Boc-2-phenylpiperidine and the application of this chem-
istry to a target-oriented synthesis of a non-racemic NK1 antagonist
2.7 Shortly after the establishment of 2 as our program lead com-
pound for in-depth medicinal study of NK1 antagonists, we also
accomplished two complimentary-modular stereoselective asym-
metric syntheses8 of 2. Armed with this chemistry, we undertook
an SAR investigation of 2 to improve its overall biological profiles.
In this Letter, we would like to disclose some amide and retroamide
derivatives that demonstrated excellent in vitro and in vivo activity
and pharmacokinetic profiles.
F3C
F3C
5
2
CF3
CF3
2
HN
Ph
HN
Ph
O
O
1
Ki (NK1 ) = 1.0 nM
2
Ki (NK1 ) = 0.3 nM
Figure 1.
When 2 was first discovered, it was shown that this compound
had a poor pharmacokinetic (PK) profile and poor in vivo activity in
gerbil foot thumping (GFT) model. We were inspired by the earlier
work on the 4,4-substituted piperidine NK1 antagonist9 and
decided to introduce some polar groups to the 5 position of piper-
idine ring. The synthesis commenced from the key intermediate 3
from our asymmetric synthesis of 2.8 The olefin was ozonolyzed
followed by TBAI reduction to afford the corresponding aldehyde,
which upon treatment of Wittig reagent methyl 2-(tert-butoxycar-
bonylamino)-2-(dimethoxyphosphoryl)acetate and DBU to afford
4. Compound 4 was then hydrogenated and subsequently reacted
with HCl to remove two nitrogen protecting groups. Further treat-
ment with base resulted in cyclization to lactam 5. Subsequent
reduction using LAH/AlCl3 produced a diamine which was selec-
tively acylated at the primary amine to afford a series of amides.
Initially, the mixture of diamines was acetylated to afford a pair
of diastereomers 6a and 6b, which were then separated by HPLC.
The relative stereochemistry of these amides was determined by
NOE study (Scheme 1).
q
Part of this work has been presented at 232nd ACS National Meeting, San
Francisco, CA, United States, Sept. 10-14, 2006: MEDI-476.
* Corresponding author. Tel.: +1 908 740 4484.
E-mail address: dong.xiao@merck.com (D. Xiao).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.08.059

6314
D. Xiao et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6313–6315
SOtBu
CO2Me
O
NHSOtBu
HN
O
Ph
Ph
HN
O
R1
NH
Ph
Ph
1) O3
2) TBAI
NH2
1) LAH/AlCl3
NHBoc 1) H2, Pd/C
2) HCl/dioxane
O
O
CF3
CF
2) derivatization
3
CF3
CF3
3) DBU
CO2Me
NHBoc
3
(MeO)2OP
4
5
6
CF3
CF3
CF3
CF3
Scheme 1.
Although the in vitro NK1 potencies10 of the two isomers were
similar, the in vivo activity showed marked difference. The (R) iso-
mer 6a was much more potent in GFT assay11 with better rat PK
profile,12 therefore, the subsequent study was concentrated on
the (R) derivatives. It was interesting to note that although the
binding activities were similar throughout the series, the in vivo
GFT activity deteriorated with the increase of molecular weight
from 6a to 6c–6e. Unlike in vitro assay, the potency of GFT assay
also displayed remarkable preference towards amide moiety, since
the ureas 6f and 6g were less potent. Similarly, sulfonamide 6h and
imine mimics of carbonyl analogs 6i and 6j reduced GFT activity
dramatically (Table 1).
The most potent acetamide 6a was investigated extensively.
Additional PK study established its half-life as 3.2 h and bioavail-
ability at 63% in rat. However, it was found that 6a was metabo-
lized in vivo to diamine 7, which, as shown in Scheme 2,
accumulated in rat brain (Fig. 2). This phenomenon has been ob-
served for a number of dibasic amines and was believed to likely
cause phospholipidosis.13–15
Confronted with undesirable metabolism of amide analogs, we
sought to eliminate the liability by introducing retroamide analogs.
If retroamides undergo similar in vivo degradation, the metabolites
would be a series of aminoacids, which should be eliminated more
readily. The retroamides were synthesized from the common inter-
mediate 3 through an alkylation/olefin metathesis16 as the key step
for piperidine ring closure. Further elaboration of the intermediate
8 afforded the desired retroamides 9 (Scheme 3).
Table 1
R1
F3C
CF3
HN
O
Ph
Entry
R1
Ki (NK1)
(nM)
GFT at 4 h
Rat AUC (0–6, po)
at 10 mpk ng h/ml
The retroamides 9 were generally potent NK1 antagonists.
Unlike the amide analogs, the two diastereomeric retroamide ser-
ies did not show a profound difference in their in vivo activity.
However, in the same diastereomer series, the interesting trend
of decreasing in vivo activity with increase of molecular weight
was observed again. The lead analog 9a, demonstrated most potent
in vitro and in vivo activity, with a good PK profile and bioavailabil-
ity of 65% in rat (Table 2).
NH
O
6a
0.15
100% at 1 mpk
10,040
99% at 0.3 mpk
83% at 0.1 mpk
T1/2 = 3.2 h, BA = 63%
NH
O
6b
6c
0.35
0.29
76% at 1 mpk
795
36% at 0.3 mpk
NH
O
100% at 1 mpk
1947
HN
O
HN
O
Ph
Ph
NHAc
CF3
NH2
CF3
in vivo
93% at 0.3 mpk
50% at 0.1 mpk
degradation
NH
O
6d
0.23
100% at 1 mpk
79% at 0.3 mpk
5263
6a
7
CF
CF3
3
Scheme 2.
N
6e
6f
0.26
0.69
61% at 1 mpk
13,828
6035
O
NH
Brain/Plasma of Metabolite 7 in rat @ 3 mpk (po) dosing
Brain(ng/ml) Plasma(ng/mL) B/P ratio
NH2
NH
96% at 1 mpk
6% at 0.3 mpk
35
30
25
20
15
10
5
800
700
600
500
400
300
200
100
0
O
N
O
6g
6h
0.59
1.03
86% at 1 mpk
ND
71% at 0.3 mpk
NH
90% at 1 mpk
5943
SO2Me
25% at 0.3 mpk
NH
N
O
6i
6j
0.33
0.28
5% at 1 mpk
ND
ND
N
0
0
12
24
36
48
60
72
84
96
NH
N
Time Post Dose (hr)
37% at 1 mpk
Figure 2. Brain/plasma of metabolite 7 in rat at 3 mpk (po) dosing.

D. Xiao et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6313–6315
6315
SOtBu
N
NHSOtBu
Ph
HN
O
Ph
R2
Ph
1) NaH
Br
CO2Et
1) NHRR',Me3Al
2) H2, Pd/C
O
O
CF
CO2Et
3
CF3
CF3
3) HCl/dioxane
2) Grubbs'2nd
generation catalyst
9
3
8
CF3
CF3
CF3
Scheme 3.
Table 2
Acknowledgments
R2
F3C
The authors thank Dr. John J. Piwinski for supporting this re-
search program and Dr. Jonathan R. Young for helpful comments
on this Letter.
CF3
HN
Ph
O
Entry
R2
Ki (NK1)
(nM)
GFT at 4 h
Rat AUC (po)
ng h/ml
References and notes
1. Jones, S.; Gibbins, J. M. Curr. Opin. Pharmacol. 2008, 8, 114.
2. Alvaro, G.; Di Fabio, R. Curr. Opin. Drug Discovery Dev. 2007, 10, 613.
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Tetrahedron: Asymmetry 2006, 17, 2596.
O
9a
0.22
0.19
0.26
92% at 1 mpk
2600 at 5 mpk, 24 h
NH2
82% at 0.3 mpk
T1/2 = 3.4 h, BA = 68%
O
9b
9c
90% at 1 mpk
1693 at 10 mpk, 6 h
NH2
75% at 0.3 mpk
O
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91% at 1 mpk
ND
HN
10. NK1 assay: Binding data are the average of two or three independent
determinations. Receptor binding assays were performed on membrane
preparations from CHO cells in which recombinant human NK1 receptors
were expressed. [3H]-Sar-Met substance P was used as the ligand for the NK1
assay, at concentrations near the experimentally derived Kd value. Ki values
were obtained using the Cheng and Prusoff equation. Cascieri, M. A.; Macleod,
A. M.; Underwood, D.; Shiao, L. L.; Ber, E.; Sadowski, S.; Yu, H.; Merchant, K. J.;
Swain, C. J.; Strader, C. D.; Fong, T. M. J. Biol. Chem. 1994, 269, 6587.
11. Fordetermination of GerbilFoot Thump(GFT) activity:TheNK1 agonist GR73632
29% at 0.3 mpk
O
9d
9e
0.56
0.37
80% at 1 mpk
166 at 10 mpk, 6 h
3676 at 10 mpk, 6 h
HN
O
92% at 1 mpk
HN Et
O
28% at 0.3 mpk
(3 pmol in 5 ll) was administered centrally to female Mongolian gerbils via icv
injection. Immediately following recovery from the anesthesia, gerbils were
placed into clear Plexiglas boxes for 5 min, and the duration of foot tapping was
measured. Foot tapping was defined as rhythmic, repetitive tapping of the hind
feet. NK1 antagonists were administered orally in 0.4% methylcellulose in
distilled water at the dose indicated at various pretreatment times prior to
injection of GR73632. Data are expressed as a percent decrease (% inhibition) in
the amount of time spent foot tapping compared to vehicle-treated controls.
Rupniak, N. M. J.; Williams, A. R. Eur. J. Pharmacol. 1994, 265, 179.
12. The rat PK assay was run at 10 mpk (unless otherwise specified) using oral
dosing with 20% HPBCD as vehicle. AUC was determined from 0 to 6 h. For
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Pharmacol. 2007, 73, 1084.
9f
1.13
0.34
0.40
78% at 1 mpk
45% at 1 mpk
69% at 1 mpk
ND
HN Et
O
9g
9h
1939 at 10 mpk, 6 h
ND
HN
O
HN
In conclusion we presented two series of piperidine NK1 antag-
onists, which demonstrated potent in vivo and in vitro activity.
They also have distinct metabolic pathways. Further optimization
of these analogs to obtain drug candidates with optimum
in vitro, in vivo and pharmacokinetic properties will be reported
in due course.
14. Gum, R. J.; Hickman, D.; Fagerland, J. A.; Heindel, M. A.; Gagne, G. D.; Schmidt, J.
M.; Michaelides, M. R.; Davidsen, S. K.; Ulrich, R. G. Biochem. Pharmacol. 2001,
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