Lactams as prostanoid receptor ligands. Part 4: 2-Piperidones as selective EP4 receptor agonists

Article abstract of DOI:10.1016/j.bmcl.2005.03.059

2-Piperidones were prepared bearing heptanoic acid or a thioether heptanoic acid at the 1-position as well as appropriately substituted at the 6-position to mimic the structure of prostaglandins. The stereochemical purity at the 6-position was determined to be ≥95% ee for an advanced synthetic intermediate. The 2-piperidones were identified as potent agonists at the EP₄ prostanoid receptor. They displayed a high affinity (K _i 5-130 nM) at EP₄ and subtype selectivity.

Full text of DOI:10.1016/j.bmcl.2005.03.059

Bioorganic & Medicinal Chemistry Letters 15 (2005) 2523–2526
Lactams as prostanoid receptor ligands.
Part 4: 2-Piperidones as selective EP4 receptor agonists
Todd R. Elworthy,* Emma R. Brill, Christopher C. Caires, Woongki Kim,
Leang K. Lach,à Jahari Laurant Tracy and San-San Chiou§
Roche Palo Alto, Department of Medicinal Chemistry, 3431 Hillview Avenue, Palo Alto, CA 94304-1397, USA
Received 10 January 2005; revised 14 March 2005; accepted 16 March 2005
Available online 11 April 2005
To the memory of Woongki Kim, deceased 28 February 2005, a valued and dedicated colleague
Abstract—2-Piperidones were prepared bearing heptanoic acid or a thioether heptanoic acid at the 1-position as well as appropri-
ately substituted at the 6-position to mimic the structure of prostaglandins. The stereochemical purity at the 6-position was deter-
mined to be P95% ee for an advanced synthetic intermediate. The 2-piperidones were identified as potent agonists at the EP4
prostanoid receptor. They displayed a high affinity (Ki 5–130 nM) at EP4 and subtype selectivity.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
findings predate our current understanding of the plu-
rality of EP receptor subtypes and the cellular effects fol-
Prostaglandin E2 (PGE2) acts on cells through at least
four distinct receptors: the prostanoid EP1, EP2, EP3,
and EP4 subtypes. Cyclohexanone 1, a ring homologue
of PGE1, was reported in 1979 Ôto be less effective than
the corresponding five-remembered ring counterpartsÕ
when tested under two in vivo settings.1 However, these
i) HOAc, reflux
O
ii) TMSCHN2
iii) NaH-KI / DMF
OTIPS
CO2H
OTIPS
CO2H
N
Br
E
rac-3
H2N
CO2H
iv) K2CO3
aq. MeOH
NH2
Ph
recryst. from
O
O
O
O
7
7
EtOAc, 4x
then free acid
(-)
OH
OH
N
1
1
(+)
15
O
HO
OTIPS
CO2H
1
2
OH
OH
N
Figure 1. Structures of 1 and 2.
R-3
i-BuC(O)Cl
Keywords: 2-Piperidone; EP4 agonist; Selective EP4 ligands; d-Lactams
as prostanoids.
then NaBH4
0o to rt
i) HOAc, reflux
ii) TMSCHN2
iii) NaBH4
*
Corresponding author. Tel.: +1 650 852 3159; fax: +1 650 354
2442; e-mail: todd.elworthy@roche.com
O
CO2H
OTIPS
OH
Roche 2002 Summer Intern (Medicinal Chemistry). Present address:
Department of Chemistry, Stanford University, Stanford, CA 94305,
United States.
N
iv) EVE, cat TFA, rt
v) NaH-KI, E / DMF
vi) PPTS / EtOH
80o, 45 min
à Present address: ARYx Therapeutics, 2338 Walsh Ave., Santa Clara,
CA 95051, United States.
H2N
CO2H
4
[α]D -37.5o
§
´
Present address: Elan Pharmaceuticals, 800 Gateway Blvd., South
San Francisco, CA 94080, United States.
Scheme 1. Preparation of N-substituted 6R-hydroxymethyl 2-piperidone.
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.03.059

2524
T. R. Elworthy et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2523–2526
Table 1. EP prostanoid receptor profile of d-lactams
Binding affinity, Ki (nM)a
Activity, EC50 (nM)a EP4
O
Compound
X
CO2H
X
EP2
EP3
EP4
N
7
S
S
S
>10,000
3800
>10,000
>10,000
ndc
21 (6)
190 (6)
34 (6)
OH
OH
8
7.3
86
Me Me
9b
>10,000
290 (6)
OH
10b
11
S
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
nd
17
260 (9)
44 (9)
44 (9)
280
OH
OH
OMe
OMe
S
22
12
C
C
8.7
7.4
OH
OH
Me
13
>10,000
OH
Me
14
15
C
C
>10,000
>10,000
nd
130
25
1730 (9)
110 (9)
Me
OH
Me
OH
OH
O
> 10,000
OH
OH
Me
16
17
18
C
S
nd
nd
nd
21,000 (6)
630 (9)
CF3
>10,000
1600
>10,000
>10,000
105
O
OH
Me
S
4.8 (6)
6.1 (6)
OH
Cl
a The values are the average of three determinations except where noted in parentheses.
b The straight line denotes a dr of 1 (at the hydroxyl carbon) for the ligand.
c nd = Not determined.
lowing EP4 activation.2 We, and others, have recently
reported that the chemically simplified 8-aza-11-deoxy-
2. Results and discussion
prostaglandin E1 2 and related c-lactams are selective
ligands for the EP4 receptor.3 Thus, we investigated
the question whether the ring homologue of 2 would
also be an agonist for the EP4 subtype. The focus of this
letter is to describe the preparation, establishment of
stereochemical purity (at the 6-position of the d-lactam
system) and selected in vitro pharmacological data of
2-piperidone ligands (Fig. 1).
The generation of the substituted d-lactam 4 is outlined
in Scheme 1 and was achieved via two routes. Lactam 4
was the pivotal intermediate to access the thioether lac-
tams (see Table 1). Classical resolution of rac-3, derived
from racemic 2-aminoadipic acid, was accomplished
using (S)-(À)-a-methyl benzylamine.4 (R)-3 could be
enriched to 95% ee.5 This optical purity is comparable
to the 98% ee5 obtained for 4 following the process of

T. R. Elworthy et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2523–2526
2525
leads to more potent agonists at EP4.3a,c,9 Ligands termi-
nated in cyclobutyl and appropriate meta-substituted
phenyl confer high activity. Biphenyl bearing ligands
15 and 18 display high potency consistent with our ear-
lier findings.9 Furthermore; similarities are seen between
the d-lactams and the recently reported cyclopentanone
derivatives. The decrease in potency observed for 12, 13,
and 14 supports the binding model of the distal features
of the x-chain proposed by Maruyama et al. 10 whereas
the meta-methoxymethyl of 12 is preferential. In con-
trast, enhancement of activity was not observed for the
d-lactams when the carbon at the 5-position of the upper
chain is replaced by sulfur. Fivefold improvement was
seen for the c-lactams3e whereas d-lactams 11 and 12
are equipotent.
i) Swern Oxid'n
ii) LiCl / i-Pr2NEt
O
P
O
O
O
OH
OH
O
N
5
4
iii) 10 mol% (R)-2-methyl-CBS
6
70 mol% BH3 SMe2, 0o, 20 min
.
iv) TBAF / THF, rt, 3 h
v) MsCl / Et3N, -20o
vi)
O
1
7
CO2H
S
N
CO2Me
KS
4
6
vii) NaOH, aq. MeOH
7
OH
Scheme 2. Preparation of thioether piperidone ligands.
3. Conclusions
cyclodehydration of (R)-2-aminoadipic acid (Scheme 1,
lower).6 In addition, (6R)-hydroxymethyl-2-piperi-
done7a was used to supplement our supply of 4 as
well as to generate the all-C ligands described in this
letter.
Elaborated 2-piperidones act as potent agonists at the
EP4 prostanoid receptor and are typically 500-fold selec-
tive for that subtype. When compared to their 2-pyrro-
lidinone counterparts, a loss of 2- to 10-fold in both
activity and affinity at the EP4 receptor is observed. Be
that as it may, we were surprised to find that 2-piperi-
done ligands display functional potency at EP4 despite
the conspicuous absence of reports of active cyclohexa-
none prostaglandins. It is not clear whether ring homo-
logues were not previously pursued because they were
investigated in systems not sensitive to the then un-
known EP4 receptor or whether the carbocyclic homo-
logues suffer significantly reduced activity as compared
to the lactams. The coplanarity of the C-7 to N-8 bond
of the d-lactam presents differences to that of the tetra-
hedral presentation of the upper side chain of synthetic
cyclohexanone 1. These differences likely reside in the
placement of the carboxylate at C-1 and its relation to
the carbonyl at C-9. Those requirements for receptor
activation are apparently preserved while accommodat-
ing the ring homologue.
The all-C a-chain ligands (12–16 of Table 1) as well as
the requisite ketophosphonates (e.g., 5 of Scheme 2)
were prepared similarly to our previously described
work on the c-lactams.8 The preparation of the more
complex 5-thia derivatives via diol 6 is detailed in
Scheme 2. Oxidation of 4 to its aldehyde and condensa-
tion with 5 afforded an enone which was treated with
borane and (R)-2-methyl oxazaborolidine [(R)-2-
methyl-CBS from Aldrich Co.]. The desired allylic alco-
hol was purified to >94% dr (silica gel chromatography,
eluant: 4% i-PrOH in 3:1 ethyl acetate:hexane)8 and
exposure to tetrabutylammonium fluoride reveals diol
6. Generation of the ligand 7 from diol 6 without resort-
ing to a secondary hydroxyl blocking group is
representative.
The 2-piperidone ligands were first evaluated for their
functional activity at the EP4 receptor9 and then profiled
for their affinity at the available EP receptors. We
elected not to assay these acids for affinity at the EP1
based on earlier findings that related c-lactams failed
to display measurable affinity for that receptor.3c,9
Acknowledgments
We are grateful for the expertise and support of Drs.
Zafrira Avnur and Keith A. M. Walker during the
course of this discovery effort.
The data in Table 1 demonstrate the 2-piperidones are
ligands with a high affinity (Ki 5–130 nM) at the EP4
receptor and behave as agonists. Ligands 9 and 10 high-
light the tolerance of substitution at an x-chain position
to potentially block PG-based metabolism and retain
agonist activity. A polar feature is also tolerated at the
terminus of the x-chain as illustrated by the phenolic li-
gands 13 and 15. However, the feature does not enhance
agonist activity as exemplified by the comparison of
pairs 12 and 13 or 15 and 18. Potency is lost for a ligand
bearing a carbonyl in replacement for the hydroxyl (e.g.,
15 vs 16). Heteroaryl terminated ligands display modest
potency (e.g., 17).
References and notes
1. Floyd, M. B.; Weiss, M. J. J. Org. Chem. 1979, 44, 71;
During the review process, one additional report of Ôless
potentÕ cyclohexanone PGE2 derivatives came to our
attention: Crossley, N. S. Tetrahedron Lett. 1971, 3327. In
the latter report, the ring hydroxyl is disposed c- to the
carbonyl and cis-5,6-unsaturation to the a-chain is pres-
ent, thus presenting two changes to 1.
2. Bos, C. L.; Richel, D. J.; Ritsema, T.; Peppelenbosch, M.
P.; Versteeg, H. H. Int. J. Biochem. Cell Biol. 2004, 36,
1187.
3. (a) Cameron, K. O.; Lefker, B. A.; Crawford, D. T.;
DaSilva-Jardine, P.; DeNinno, S. L.; Gilbert, S.; Grasser,
W. A.; Ke, H. Z.; Lu, B.; Owen, T. A.; Paralkar, V. M.;
Pharmacological similarities between the c- and d-lac-
tams are revealed for some x-chain substitutions, which

2526
T. R. Elworthy et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2523–2526
Thompson, D. D.; Tjoa, C. M.; Zamistoski, M. P.
resolved by chiral stationary phase HPLC with a Chiralcel
AD column, eluant: 3% i-PrOH in n-hexane at 1.0 mL/
min. Enantiomeric excesses reported for Scheme 1 mate-
rials were based on their respective conversion to enriched
19. This ketone was chosen to assess ee due to the ease UV
detection and the stringency of being an advanced
intermediate of the sequence that is not susceptible to
racemization.
Abstracts of Papers, 224th National Meeting of the
American Chemical Society, Boston, MA; American
Chemical Society: Washington, DC, 2002; Abstract
MEDI-307; (b) Maruyama, T.; Kobayashi, K.; Maruyama,
T. WO 2002/24647; Chem. Abstr. 2002, 136, 279265; (c)
Billot, X.; Chateauneuf, A.; Chauret, N.; Denis, D.; Greig,
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Zhao, Z.; Bao, B.; Brugger, N.; Fischer, D.; Giachetti, C.;
Golzio, L.; Karra, S.; Marinelli, P.; McKenna, S.; Palmer,
E.; Reddy, A.; Xiao, Y.; Araldi, G. Abstract of Papers, 29th
National Medicinal Chemistry Symposium, Madison, WI;
American Chemical Society: Washington, DC, 2004;
Abstract 73; (e) Elworthy, T. R.; Brill, E. R.; Chiou, S.
-S.; Chu, F.; Harris, J. R.; Hendricks, R. T.; Huang, J.;
Kim, W.; Lach, L. K.; Mirzadegan, T.; Yee, C.; Walker, K.
A. M. J. Med. Chem. 2004, 47, 6124.
O
OTIPS
N
O
F
19
O
.
6. Greenstein, J. P.; Birnbaum, S. M.; Otey, M. C. J. Am.
Chem. Soc. 1953, 75, 1994.
7. (a) Davies, C. E.; Heightman, T. D.; Hermitage, S. A.;
Moloney, M. G. Synth. Commun. 1996, 26, 687. Our
application of D-lysine monohydrochloride (Aldrich) by
this approach afforded (R) methyl 6-oxopipecolate: [a]D
+12.0 (c 1.0, CHCl3); (b) Hodgkinson, T. J.; Shipman, M.
Synthesis 1998, 1141.
8. See Ref. 3e and Refs. 9(a) and 10 therein.
9. See Ref. 3e and Ref. 9(a) therein.
10. Maruyama, T.; Asada, M.; Shiraishi, T.; Ishida, A.;
Yoshida, H.; Maruyama, T.; Ohuchida, S.; Nakai, H.;
Kondo, K.; Toda, M. Bioorg. Med. Chem. 2002, 10, 989.
4. Scribner, R. M. U.S. Patent 4,321,201, 1982; Chem. Abstr.
1982, 97, 455567. (R)-(+)-a-Methylbenzylamine was used
to resolve an N-alkyl substituted 5-carboxylic acid of 2-
pyrrolidinone to furnish enriched (5R) acid c-lactam. The
5R configuration is presumed based bioassay
determination.
5. d-Lactam 4 displays a rotation of [a]D À37.5 (c 1.0,
CH3CN) when prepared from (R)-2-aminoadipic acid
(Sigma–Aldrich) and corresponds to 98% ee. Ketone 19
was produced8 to assess enantiomeric purity and was