Substituted piperidinyl glycinyl 2-cyano-4,5-methano pyrrolidines as potent and stable dipeptidyl peptidase IV inhibitors

Article abstract of DOI:10.1016/j.bmcl.2013.01.104

Synthesis and structure-activity relationship of a series of substituted piperidinyl glycine 2-cyano-4,5-methano pyrroline DPP-IV inhibitors are described. Improvement of the inhibitory activity and chemical stability of this series of compounds was respectively achieved by the introduction of bulky groups at the 4-position and 1-position of the piperidinyl glycine, leading to a series of potent and stable DPP-IV inhibitors.

Full text of DOI:10.1016/j.bmcl.2013.01.104

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1622–1625
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Substituted piperidinyl glycinyl 2-cyano-4,5-methano pyrrolidines as
potent and stable dipeptidyl peptidase IV inhibitors
⇑
Guohua Zhao , Chet Kwon, Aiying Wang, James G. Robertson, Jovita Marcinkeviciene, Rex A. Parker,
Mark S. Kirby, Lawrence G. Hamann
Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08543-5400, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis and structure–activity relationship of a series of substituted piperidinyl glycine 2-cyano-4,5-
methano pyrroline DPP-IV inhibitors are described. Improvement of the inhibitory activity and chemical
stability of this series of compounds was respectively achieved by the introduction of bulky groups at the
4-position and 1-position of the piperidinyl glycine, leading to a series of potent and stable DPP-IV
inhibitors.
Received 24 August 2012
Revised 18 January 2013
Accepted 22 January 2013
Available online 31 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Piperidine
Pyrrolidine
Dipeptidyl peptidase IV inhibitor
Type 2 diabetes
Type 2 diabetes mellitus is a chronic disorder currently affecting
approximately 366 million people worldwide of which the preva-
lence continues to rise every year.1 Current primary treatments,
originally discovered serendipitously, rely on insulin secretagogues
and insulin sensitizers. Unfortunately, since these treatments are
often associated with undesired side effects such as hypoglycemia,
edema, and weight gain significant unmet medical need remains
for novel effective drugs to treat the underlying disease.2 The clin-
ically validated target, serine exopeptidase dipeptidyl peptidase IV
(DPP-IV, EC 3.4.14.5, CD), has received much attention for the
treatment of type 2 diabetes.3 DPP-IV is widely expressed on epi-
thelial or endothelial cells of a variety of different tissues including
kidney and intestinal brush border membranes.4
Type 2 diabetes also contributes to the pathophysiology of car-
diovascular diseases (CVD). Emerging data support the idea that
potentiating the levels of some DPP-IV natural substrates may be
associated with cardio-protective effects. In the saxaglitpin clinical
program, no increased risk of CV death, myocardial infarction, or
stroke was seen in saxagliptin treatment groups across the entire
program, supporting a hypothesis that saxagliptin may reduce CV
events.5 While the possible role DPP-IV inhibitors in CVD treat-
ment will require additional clinical study, it is notable that the
receptor for GLP-1 is expressed in cardiac tissue, and that GLP-1
is cardio-protective in some experimental ischemia/reperfusion
models.6 Other potential DPP-IV substrates relevant to CVD include
stromal cell-derived factor-1 (SDF-1), which improves cardiac
function and may reduce apoptosis of cardiomyocytes, and in-
creases angiogenesis after experimental coronary artery occlu-
sion.7 Another is the chemokine Regulated on Activation Normal
T-cell Expressed and Secreted (RANTES). Low plasma RANTES lev-
els are associated with cardiac mortality in angiography patients
(including diabetic men),8 and genetic polymorphisms that cause
lower RANTES levels are associated with increased CV mortality
in diabetics and end stage renal disease patients.9
Incretins, such as glucagon-like peptide 1 (GLP-1) and gastric-
inhibitory polypeptide (GIP), promote the secretion of insulin in re-
sponse to nutrient ingestion. DPP-IV mediated cleavage of a N-ter-
minal dipeptide from incretins with proline or alanine at the
penultimate position abrogates this signaling. Therefore, inhibition
of DPP-IV mediated incretin degradation represents a mechanistic
approach for the treatment of type 2 diabetes. DPP-IV inhibitors
have demonstrated robust antidiabetic efficacy in the clinic.10 Both
dipeptidic inhibitors vildagliptin11 and saxagliptin,12 and the non-
peptidic sitagliptin13 and linagliptin14 have received FDA and/or
EMEA approval for treatment of type 2 diabetes (Fig. 1). Other
DPP-IV inhibitors including alogliptin15 have advanced into late
stages of clinical development.16
A variety of small-molecule inhibitors of DPP-IV have been dis-
covered in the last two decades.17 The majority of known inhibitors
resemble the N-terminal dipeptide residues of the enzymatic sub-
strates: a penultimate N-terminal proline mimic at the P1 position
joined to an additional L-amino acid or similar surrogate at the P2
position. Many potent reversible DPP-IV inhibitors contain cyano-
⇑
Corresponding author. Tel.: +1 609 818 5553.
E-mail addresses: guohua.zhao@bms.com, zhaog@bms.com (G. Zhao).
pyrrolidine P1 group as proline mimics.18 It is generally believed
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.01.104

G. Zhao et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1622–1625
1623
O
N
N
N
N
N
R'
HO
R'
N
H
N
N
O
N
N
CN
O
H2N
NH2
compound
2
3
4
5
CN
O
vildagliptin
EMEA approved
linagliptin
FDA approved
Ki (nM)
26
109
695
1201
Figure 3. Some early 2-cyano-4,5-methano pyrrolidine DPP-IV inhibitors with a
variety of P2 moieties.
F
F
F
O
NH2
HO
H2N
N
N
N
Our prior investigation of acylated 2-cyano-4,5-methano pyr-
rolidines had revealed two important constraints regarding the
P2 position: (1) the fourfold greater potency obtained following
N
N
CN
O
CF3
saxagliptin
EMEA/FDA approved
sitagliptin
EMEA/FDA approved
condensation with L-valine (2) rather than L-leucine (3) suggested
the P2 site preferentially accommodated sterically less demanding
substituents at the opening (Fig. 3); (2) the even greater 25- to 50-
Figure 1. Approved DPP-IV inhibitors as type 2 diabetes medications.
fold reduction in potency upon incorporation of
L-phenylglycine
(4) or its biphenyl analog (5) relative to -valine (2) suggested that
L
that covalent binding of this nitrile group with the catalytically ac-
tive site Ser630 hydroxyl contributed to the potency of these DPP-
IV inhibitors (Fig. 2). However, the nitrile group was also responsi-
ble for chemical instability noted for the early nitrile-based inhib-
itors, whereby the free amine intramolecularly cyclized with the
nitrile, forming inactive cyclic imidates and/or diketopiperizines
after hydrolysis. This issue has been largely solved by further struc-
ture modifications employing various combinations of sterically
hindered P1 and P2 residues, use of conformationally constrained
amide bond mimics, and removal or replacement of the nitrile
group, to avoid or block the cyclization reaction. Although these
modifications significantly attenuated the potency of natural ami-
no acid-based inhibitors, the potency was restored upon incorpora-
tion of an optimized unnatural amino acid at the P2 position.
In contrast to the strict steric limitation of the P1 position, a
wide range of functionalities are tolerated at the P2 position. The
preferred b-branching at this position not only improved chemical
stability but also enhanced potency. Moreover, the X-ray crystallo-
graphic finding of the deep S2 pocket in the enzyme suggested that
binding activity should be increased if a large elongated P2 substi-
tuent completely filled this pocket.19 However, this goal was not
realized by a large number of small molecule inhibitors that intro-
duced steric bulk at the b-position.17,18 Likewise an attempt to
completely fill the S2 pocket by designing a flexible linearly ex-
tended P2 substituent failed due to the propensity of the assem-
blage to adopt a folded conformation.20
a nonplanar constrained elongated substituent would be prefera-
ble. Accordingly we envisioned that merging the valine and phen-
ylglycine moieties to generate a 4-piperdinyl glycine moiety (1)
would provide a constrained spacer amenable for attachment of
progressive larger substituents that might fully occupy the deep
S2 pocket. Our strategy involved sequential evaluation of the effect
of substituents at the 1-position and 4-position of the piperdine to
enhance inhibitory activity and improve chemical stability prior to
identification of potent and chemically stable inhibitors produced
by optimal additive effects from both positions.
Herein we describe the synthesis and structure-activity rela-
tionship of a series of DPP-IV inhibitors by conjugation of substi-
tuted piperidinyl glycines with 2-cyano-4,5-methano pyrrolidine.
2-Cyano-4,5-methano pyrrolidine 8 was prepared from amide 621
using Ashworth’s procedure22 (Scheme 1). Protection of the proline
nitrogen with 2-nitro-phenylsulfenyl group followed by dehydra-
tion with POCl3 and imidazole gave nitrile 7. Subsequent acidic
deprotection afforded 2-cyano-4,5-methano pyrrolidine 8 in excel-
lent yield.
The 4-piperidinyl glycine derivatives 1a–1t (Table 1) were pre-
pared as described in Scheme 2. Coupling of commercially avail-
able Fmoc-N-4-Boc piperidinyl glycine
9 with 2-cyano-4,5-
methano pyrrolidine 8 followed by de-protection of the Boc group
gave key intermediate 10. Introduction of different functional
groups by respective reductive amination, acylation, thioacylation,
or sulfonylation and subsequent removal of the Fmoc protecting
group provided compounds 1b–1t, whereas direct Fmoc group
deprotection of intermediate 10 afforded compound 1a in good
yield.
Ser630
The synthesis of compounds 15a–15d utilized the Claisen rear-
rangement to introduce the b quaternary center (Scheme 3).12
Beginning with commercially available ester 11, DIBAL-mediated
reduction followed by coupling with Cbz-glycine and subsequent
Claisen rearrangement generated the vinyl intermediate acid 12
in good yield. Coupling of acid 12 with compound 8 yielded the
key intermediate amide 13. Amide 13 was separated by chiral
R
R
HO
Ser630
N
N
H2N
H2N
S2
CN
O
O
N
O
R4
N
HN
trans
P2
R1
P1
N
H2N
O
R
N
O
R
CN
S1
O
c
a, b
CONH2
CN
1
, R1 = H
NH2
cis
N
H
X
HCl
HN
HN
N
15, R1 = Et
S
CN
CN
NO2
X = NH, amidine
X = O, diketopiperidine
6
7
8
Figure 2. Potency and instability of cyanopyrrolidine dipeptidic inhibitors and
Scheme 1. Reagents and conditions: (a) 2-nitrophenylsulfenyl chloride, Et3N,
opportunities for optimization.
CH2Cl2 (64%); (b) POCl3, imidazole, pyridine (94%); (c) 4 N HCl, dioxane, Et2O (91%).

1624
G. Zhao et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1622–1625
Boc
Table 1
H
N
DPP IV inhibitory activity for compound 1
N
a, b
Compound
–R4
–H
DPP-IV Kia (nM)
1a
1b
98
75
7
5
Fmoc
OH
Fmoc
N
N
H
N
H
t-Bu
t-Bu
CN
O
O
O
9
10
1c
25
23
1
2
O
R4
N
O
S
c and/or d
t-Bu
t-Bu
1d
N
H
N
H2N
CN
O
1e
1f
18
14
1
1
1
N
H
Scheme 2. Reagents and conditions: (a) compound 8, PyBOP, DIEA, CH2Cl2 (78%);
(b) 4 N HCl, dioxane (quantitative); (c) couple R4: aldehyde, NaBH(OAc)3, AcOH,
CH2Cl2 or PyBOP, DIEA, CH2Cl2 or isocyanate, Et3N, CH2Cl2 or thioisocyanate, Et3N,
CH2Cl2 or sulfonylchloride, DIEA, CH2Cl2; (d) piperidine, CH2Cl2.
O
O
O
Me
1g
1h
1i
18
4
3
t
-Bu
0.2
1
Boc
N
Boc
N
Boc
N
t
-Bu
O
O
d
4
a, b, c
OH
Cbz
N
Cbz
OH
N
N
1j
18
14
18
11
18
1
2
2
1
2
H
H
CN
O
11
O
13
O
12
O
O
1k
1l
R4
N
H
N
O
e, f
g, h
Cbz
N
N
O
N
H2N
H
1m
1n
Cl
CN
S
CN
O
O
15
14
O
S
O
Scheme 3. Reagents and conditions: (a) DIBAL, CH2Cl2, À40 °C to 0 °C (68%); (b)
Cbz-Gly, DCC, DMAP, CH2Cl2 (91%); (c) ZnCl2, LDA, THF, À78 °C to 0 °C (71%); (d)
compound 8, PyBOP, DIEA, CH2Cl2 (80%); (e) AD chiral HPLC separation; (f) 4 N HCl,
dioxane (quantitative); (g) couple R4: PyBOP, DIEA, CH2Cl2 or sulfonylchloride, Et3N,
CH2Cl2; (h) H2, 10% Pd/C, MeOH.
O
S
O
1o
13
2
O
O
O
O
O
Table 2
1p
1q
1r
30
8
2
DPP IV inhibitory activity for compound 15
N
CF3
Compound
–R4
DPP-IV Kia (nM)
35
N
N
O
0.4
0.1
15a
1
t-Bu
N
O
15b
38 0.4
5
N
O
S
O
O
N
N
N
N
15c
15d
15
10
2
4
Cl
O
1s
1t
4
2
1
S
a
All Ki values are the mean s.d. of at least triplicate determinations.
0.5
N
All compounds were tested in vitro against purified human
a
All Ki values are the mean s.d. of at least triplicate determinations.
DPP-IV under steady state conditions with gly-pro-p-nitroanilide
as substrate as previously described.21
Our SAR study was guided by our prior findings that hydropho-
bic and/or aromatic substituents are preferred at the P2 position of
diprolyl DPP-IV inhibitors.23 Initially, we sought to extend a lipo-
philic bulky t-butyl group into the S2 pocket by employing a vari-
ety of two atom spacers to attach the t-butyl group to the
piperdine nitrogen while keeping the 1-position of the piperidine
HPLC to give the desired S-enantiomer that was subjected to Boc
deprotection to give amine 14.12,21 The introduction of different
functional groups at the 4-position as described above followed
by simultaneous Cbz deprotection and vinyl reduction under stan-
dard condition (H2, Pd/C) provided 15a–15d in good yield.

G. Zhao et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1622–1625
1625
Table 3
Solution stability of the selected compounds at pH 7.2 and 37 °C
piperidinylglycinyl-4,5-methanoprolinenitriles by employing
a
variety of spacers as H-bonding acceptors. Substituents such as
the sterically less demanding alkyl and nitrogen-containing het-
eroaryl groups confer potency in the single-digit nM range, pre-
sumably by engaging in an additional favorable non-polar
interactions and H-bonding or dipolar interactions with the S2
pocket.
Degradation half lives t1/2 (days)
10 30 50
2.0 1.6
19.7 10.2
Concenteration (mM)
Compound
1h
15a
1.6
8.0
Acknowledgment
ring unsubstituted (Table 1). The near equivalent potency of 1a
(Ki = 98 nM) and 1b suggested that the flexible pendent t-butyl
group did not interact strongly with the S2 pocket. However, the
ꢀfourfold increase in potency upon conversion of the tertiary
amine 1b to a carbamate 1c, urea 1d, or thiourea 1e suggested that
the acyl moiety acting as a hydrogen bond acceptor engaged in a
favorable interaction with some residue in the S2 pocket. This con-
clusion is underscored by the near equivalence in potency for the
acetamide 1f and pivalamide 1g. The ꢀ20-fold increase with the
amide 1h and 1i may suggest that due to the conformational
mobility arising from the intervening methylene the t-butyl group
of 1h or cyclohexyl of 1i can engage in additional favorable non-
polar interactions with the pocket which is not available to the ste-
rically more demanding adamantyl analog 1j or the more rigid aryl
amides 1k and 1l. The twofold loss in potency of 1p relative to 1k
may reflect attenuation in H-bonding acceptor capability due to
the electron deficient pyridinyl ring. Sulfonamides 1m–1o can also
serve as H-bonding acceptors thereby accounting for comparable
potency with benzamide 1k. The enhanced potency of the nitrogen
containing heterocyclic amides 1q–1t relative to benzamide 1k
may be due to additional H-bonding of S2 residues with the ring
nitrogens or favorable dipolar interactions with the heteroaryl
rings.
We thank Dr. William N. Washburn for his suggestions during
the manuscript preparation.
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ity and potency to closely related analogues,12,21 an ethyl
substituent at the 1-position of the piperidine ring attenuated po-
tency. Analogues 15a and 15b with substituents t-butylacetyl and
1-(1,6-naphthyridin-2-yl)-carbonyl exhibited a 9- and 19-fold loss
of potency respectively to their unsubstitued counterpart 1h and
1t. This reduction of potency may be in part due to the conforma-
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altering the spatial orientation of the 4-position substituents.
Interestingly, only the aryl sulfonamides (15c and 15d) maintained
comparable potency with the non-b-quaternary series, presumably
due to the flexible sulfonyl spacer enabling the 4-position substit-
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ano-4,5-methano pyrrolidines were potent DPP-IV inhibitors, the
aqueous solution stability was compared for selected examples
from both the non- and b-quaternary series. At pH 7.2 the b-ethyl
analogue 15a at concentration of 10, 30, 50 mM exhibited a half-
life which was consistently 5- to 10-fold longer than the 1.6–
2 day half-life measured for the non-b-quaternary analogue 1h
(Table 3) reflecting the expected enhanced chemical stability due
to the sterically encumbered b-quaternary center.
In conclusion, systematic variation of the angle and size of moi-
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of compounds as potent and stable DPP-IV Inhibitors. Significant
potency increases against DPP-IV enzyme were achieved with the
introduction of sterically bulky substituents at the 4-position of
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