Structure-activity-relationship of amide and sulfonamide analogs of omarigliptin

Article abstract of DOI:10.1016/j.bmcl.2015.10.070

A series of novel substituted-[(3R)-amino-2-(2,5-difluorophenyl)]tetrahydro-2H-pyran analogs have been prepared and evaluated as potent, selective and orally active DPP-4 inhibitors. These efforts lead to the discovery of a long acting DPP-4 inhibitor, omarigliptin (MK-3102), which recently completed phase III clinical development and has been approved in Japan.

Full text of DOI:10.1016/j.bmcl.2015.10.070

Bioorganic & Medicinal Chemistry Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure–activity-relationship of amide and sulfonamide analogs
of omarigliptin
a
a
a
a
a
Ping Chen a, , Dennis Feng , Xiaoxia Qian , James Apgar , Robert Wilkening , Jeffrey T. Kuethe ,
Ying-Duo Gao a, Giovanna Scapin a, Jason Cox a, George Doss d, George Eiermann b, Huaibing He d,
Xiaohua Li d, Kathryn A. Lyons d, Joseph Metzger c, Aleksandr Petrov b, Joseph K. Wu c, Shiyao Xu d,
Ann E. Weber a, Youwei Yan a, Ranabir Sinha Roy c, Tesfaye Biftu a
⇑
a Department of Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States
b Department of Pharmacology, Screening & Protein Sciences, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States
c Department of Cardiometabolic Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States
d Department of Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel substituted-[(3R)-amino-2-(2,5-difluorophenyl)]tetrahydro-2H-pyran analogs have
been prepared and evaluated as potent, selective and orally active DPP-4 inhibitors. These efforts lead
to the discovery of a long acting DPP-4 inhibitor, omarigliptin (MK-3102), which recently completed
phase III clinical development and has been approved in Japan.
Received 27 July 2015
Revised 8 September 2015
Accepted 23 October 2015
Available online xxxx
Ó 2015 Published by Elsevier Ltd.
Keywords:
DPP-4 inhibitor
Type 2 diabetes
DPP-8
DPP-9
Sitagliptin
Pyrazolopyrolidine
Omarigliptin
X-ray
Type 2 diabetes mellitus (T2DM) is a fast growing epidemic,
affecting nearly 387 million people worldwide in 2014.1 Among a
wide range of therapeutic targets, dipeptidyl peptidase IV (DPP-
4) inhibition with small molecules has become a clinically proven
therapeutic approach for the treatment of Type 2 diabetes mellitus
(T2DM).2,3 Glucagon-like peptide 1 (GLP-1) and glucose-dependent
insulinotropic polypeptide (GIP) are incretin hormones which
stimulate glucose dependent insulin secretion and slow gastric
emptying.4a,b In addition, GLP-1 has been shown to inhibit gluca-
gon secretion, reduce appetite, and stimulate the regeneration
and differentiation of islet b-cells in rodent models. However, both
hormones are rapidly cleaved to their inactive forms by the
enzyme DPP-4.4c,d Therefore, inhibition of DPP-4 can increase
levels of endogenous incretin hormones GLP-1and GIP. The DPP-
4 inhibitor program culminated in the discovery of JANUVIAÒ (sita-
gliptin phosphate) as the first FDA approved DPP-4 inhibitor for the
treatment of patients with T2DM. Subsequently, additional DPP-4
inhibitors such as vildagliptin (Novartis), saxagliptin (BMS), lina-
gliptin (Lilly) and alogliptin (Takeda) have entered market.
A conceptual cyclization of the sitagliptin core provided the
rationale to prepare structurally rigid tetrahydropyran (THP) ana-
logs (Fig. 1) and led to the identification of the dihydropyrrolopy-
razole clinical candidate 2.5 Extensive structure–activity
relationship (SAR) studies on the pyrazole ring identified several
series including amide, sulfonamide and sulfone analogs. These
efforts culminated in the discovery of the potent and selective
DPP-4 inhibitor 20, omarigliptin (MK-3102),6 which has a pharma-
cokinetic profile amenable to once weekly dosing. Omarigliptin has
completed phase III clinical development in Japan and is filed for
registration in that country. In this manuscript, we describe our
broader efforts at the optimization of the pyrazolopyrolidine series
of DPP-4 inhibitors by making several amide and sulfonamide
analogs.
Several approaches for the variation of the substituents on the
dihydropyrrolopyrazole side chain are described in Scheme 1.
Reaction of the Boc protected ketone 3 with N,N-dimethylfor-
mamide dimethylacetal (DMF-DMA) in THF generated enamine
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.bmcl.2015.10.070
0960-894X/Ó 2015 Published by Elsevier Ltd.
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2
P. Chen et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
F
F
F
R'
NH2
F
NH2
O
F
O
R
NH
N2
N
N
1
N
N
N
3
CF3
2 R' = H, R = H
20 R' = H, R = 2-SO2Me, Omarigliptin (MK-3102)
1
Sitagliptin
Figure 1. Rational design of DPP-4 inhibitors.
Boc
O
O
a
b
N
Boc
Boc
HN
N
N
NH
N
N
3
4
5
HN
c, d
SO2R'
N
N
N
N
+
SO2R'
6
7
Boc
N
O
O
O
e, f
g
H
N
BocN
NC
OMe
NC
OH
b
CN
10
8
9
N
N
d
HN
NH
Boc
Boc
N
NH
NH2
NH2
11
12
N
N
h
i
HN
NH
N
NH
11
SO2R'
SR'
14
13
Scheme 1. Preparation of substituted dihydropyrrolopyrazole intermediates. Reagents and conditions: (a) DMF-DMA, THF, 60 °C; (b) NH2NH2 (35% aq), EtOH, reflux; (c)
R0SO2Cl, NaH, acetonitrile, 60 °C; (d) TFA, CH2Cl2, rt; (e) Boc2O, DIPEA, CH2Cl2, rt; (f) CH3I, K2CO3, acetonitrile, 80 °C; (g) NaOCH3, toluene, 80 °C; (h) R0S-SR0, tBuONO, CCl4,
70 °C; (i) mCPBA, TFA, CH2Cl2, rt.
intermediate 4, which was subsequently reacted with hydrazine to
yield Boc-protected dihydropyrrolopyrazole 5. Reaction of 5 with
variety of sulfonyl chlorides in the presence of sodium hydride
afforded chromatographically separable 1- and 2-substituted dihy-
dropyrrolopyrazoles which were then treated with TFA to give key
intermediates 6 and 7. The structures of the two isomeric com-
pounds 6 and 7 were confirmed by NMR. It was observed that
under Boc deprotection conditions (TFA/CH2Cl2), only three dihy-
dropyrrolopyrazoles substituted by cyclopropyl, cyclopentyl and
N-methylimidazolyl groups at the 1-position (isomer A) were
stable. These intermediates were isolated and converted into the
corresponding DPP-4 inhibitors (25a, 26a and 27a).
3-Aminodihydropyrrolopyrazole intermediate 12 was prepared
through the route also described in Scheme 1. Reaction of
2-((2-cyanoethyl)amino) acetic acid (8) with Boc anhydride was
followed by esterification with iodomethane to afford ester 9.
Cyclization of 9 in the presence of sodium methoxide yielded
carbonium ion with an alkyl disulfide to give 13. The thiol 13
was oxidized to the sulfone 14 using mCPBA.
Pyranone key intermediate 16 was prepared from aldehyde 15
as described previously by our group.6 Reductive amination of
pyranone 16 with 1- or 2-substituted dihydropyrrolopyrazoles 6
and 7, employing decaborane in methanol, followed by removing
the Boc protecting group yielded the desired tetrahydropyran
products 17 and 18 (Scheme 2). Utilizing the same reductive ami-
nation conditions, the 3-amino pyrazole product 19 was made
from pyranone 16 and 3-amino dihydropyrrolopyrazole 12.
F
NH2
d,b
14 + 16
F
O
N
NH
N
a-cyano ketone 10. Refluxing 10 with hydrazine in ethanol fol-
40-42
lowed by TFA deprotection of the Boc group provided 3-amino
pyrazole intermediate 12. Attempts to halogenate the 3-position
of 5 were unsuccessful under a variety of reaction conditions.
Functionalization at the 3-position was accomplished by diazotiza-
tion of the aminopyrazole 11 and trapping of the intermediate
R'O2S
Scheme 2. Preparation of tetrahydropyran DPP-4 inhibitors. Reagents and condi-
tions: (a) 6 or 7, B10H14, MeOH, rt; (b) TFA, CH2Cl2, rt; (c) R’SO2Cl or (R0CO)2O, Et3N,
CH2Cl2, rt; (d) NaBH3CN, Et3N, HOAc, DMA, rt.
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P. Chen et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
3
Sulfonylation or acylation of the amino group with several sulfonyl
chlorides and anhydrides proceeded smoothly to give the desired
3-substituted pyrazole analogs 30–39 after deprotection.
Reductive amination of 16 with 14 provided the 3-methylsulfonyl,
3-isopropylsulfonyl and 3-phenysulfonyl pyrazole derivatives
40–42.
Compounds were evaluated in vitro for their inhibition of DPP-
4.7a The inhibitors were also tested against DPP-4 structural
homologs of the DPP-4 gene family, including FAP,7b,8 DPP-8,9
DPP-9,10 and QPP.7 Inhibition of DPP-8 and DPP-9 has been associ-
ated with profound toxicity in animal studies.11 While the signifi-
cance of this adverse effect in humans has not been demonstrated,
treatment-related dermatological toxicity in monkeys was
observed with non-selective DPP-4, DPP-8, and DPP-9 inhibitors.12
Further in recent cardiovascular safety studies among diabetic
patients using a selective DPP-4 inhibitor, Januvia (sitagliptin), no
increased hospitalization for heart failure was reported.13
Therefore, selectivity profiles against DPP-8 and DPP-9 is highly
inhibition and a varying degree of selectivity reduction over QPP,
DPP-8 and FAP enzymes relative to the methylsulfonamide 20.
The 1-substituted compounds 26a and 27a were slightly less
potent DPP-4 inhibitors than the corresponding 2-substituted ana-
logs 26b and 27b.
Analogs bearing an amide, sulfonamide or sulfone side chain at
the 3-position of the pyrazole moiety are summarized in Table 2. In
general, analogs 30–42 were comparable to parent compound 2 in
terms of DPP-4 potencies, although slightly reduction of selectivity
against FAP and, in certain cases, QPP and DPP-8 were observed. In
the case of amide derivatives 30–33, an increase in the size and
polarity of the amide substituents resulted in only 2- to 3-fold
decline in DPP-4 potency, as seen in 30 versus 32 and 33. However,
this trend was not observed in the sulfonamide series 34–39, spe-
cially the imidazole sulfonamide 39 which was ten times more
potent than the methylsulfonamide 34 in DPP-4 inhibition. The
attachment of electron deficient sulfonyl groups at the 3-position
of pyrazole ring 40–42 maintained excellent DPP-4 inhibitory
activities. The retention of DPP-4 in vitro potencies of analogs in
Tables 1 and 2 relative to the parent compound 2 strongly suggests
that substitution around the pyrazole ring is well tolerated.
Several representative DPP-4 inhibitors were selected for
in vivo pharmacokinetic studies in rat. PK experiments were con-
ducted using the procedure described in our previous manuscript6
and results are listed in Table 3. In general, 1- and 3-substituted
pyrazole analogs 25a, 26a, 30 and 31 gave sub-optimal PK profiles
with high clearance rates, shorter half-life and lower oral exposure
when compared to the non-substituted analog 2. However, the
cyclopropyl sulfonamide analog 25a, when administered to rats
orally, gave 79% oral bioavailability. The majority of 2-substituted
pyrazole analogs 20–26b displayed equivalent or superior PK pro-
files compared to the non-substituted analog 2.
desirable (>30 lM) for safety reasons. DPP-9 inhibition typically
tracks closely with DPP8 and thus is not reported in this
manuscript.
Results for a series of 1- and 2-substituted pyrazole sulfon-
amide analogs are listed in Table 1. In general, installation of a sul-
fonyl group at the 1- or 2-position of the pyrazole provided potent
DPP-4 inhibitory activity (DPP-4 IC50 = 0.7–7.5 nM) and desirable
off target selectivities (>4000 fold) comparable to the unsubsti-
tuted parent compound 2.5 In the case of alkylsulfonamide analogs
20–26, isopropylsulfonamide 24 was found to be the most potent
DPP-4 inhibitor (DPP-4 IC50 = 0.7 nM) while n-propylsulfonamide
23 was the least potent DPP-4 inhibitor (DPP-4 IC50 = 5.7 nM).
Two isomeric cyclopropylsulfonamides 25a and 25b were equally
potent DPP-4 inhibitors (DPP-4 IC50 = 1.6 nM) with excellent
selectivity against off targets although a slightly reduction of FAP
selectivity was seen in the isomer 25a. Increasing steric bulk to
cyclopentylsulfonyl, imidazolosulfonyl and phenyl-sulfonyl groups
(compounds 26–29) afforded compounds with the similar DPP-4
Based on the superior in vitro DPP-4 potency, off-target selec-
tivity, and rat pharmacokinetics profile, the methylsulfonamide
20, ethylsulfonamide 22 and cyclopropylsulfonamide 25b were
Table 2
3-Substituted DPP-4 inhibitors
Table 1
F
1- and 2-Substituted DPP-4 inhibitors
NH2
F
F
F
NH2
NH2
F
O
N
NH
N
F
O
O
N
N
R
N
N
N
N
Isomer
C
A
B
Isomer
Isomer
R
R
Compd
R
DPP-IV IC50 QPP IC50
DPP-8 IC50 FAP IC50
Compd
R
A/ DPP-IV IC50 QPP IC50 DPP-8 IC50 FAP IC50
(nM)
(nM)
(nM)
(nM)
B
(nM)
(nM)
(nM)
(nM)
30
31
CH3CH2CONH
c-PrCONH
1.4
1.6
>100,000 >100,000
>100,000 >100,000
47,000
22,000
2
20
21
22
23
24
25a
25b
26a
26b
H
—
B
B
B
B
B
A
B
A
B
1.4
2.6
2.3
1.8
5.7
0.7
1.6
1.6
2.6
1.6
42,000
>100,000
>100,000
>100,000
>100,000
69,000
>100,000
>100,000
54,000
>100,000
26,000
50,000
CH3SO2
CF3SO2
CH3CH2SO2
n-PrSO2
i-PrSO2
>100,000 >100,000
>100,000 >100,000
>100,000 >100,000
>100,000 >100,000
>100,000 >100,000
88,000
87,000
>100,000 >100,000
S
CONH
32
4.3
70,000
55,000
40,000
N
CONH
33
3.7
>100,000 47,000
27,000
N
c-PrSO2
>100,000
>100,000
34
35
36
37
CH3SO2NH
CH3CH2SO2NH
CF3CH2SO2NH
c-PrSO2NH
3.2
1.1
1.3
1.8
>100,000 >100,000
57,000
>100,000 >100,000
>100,000 91,000
8800
89,000
32,000
32,000
3,800
c-PentSO2
56,000
60,000
N
27a
27b
A
B
4.9
1.9
33,000
61,000
44,000
41,000
45,000
95,000
SO2NH
SO2
SO2
SO2
N
38
1.8
88,000
>100,000
60,000
N
N
28
29
B
B
2.3
1.9
95,000
25,000
>100,000
>100,000
SO2NH
39
0.3
44,000
62,000
6,300
HN
CH3SO2
i-PrSO2
C6H5SO2
40
41
42
1.7
1.7
0.4
>100,000 60,000
>100,000 >100,000
27,000
20,000
16,000
14,000
>100,000 27,000
F3C
41,000
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P. Chen et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
Table 3
Pharmacokinetic properties of selected inhibitors in rat (1 mg/kg iv and 2 mg/kg po or
0.4 mg/kg iv only)
Compd
R
Isomer Clp
(ml/min/kg)
tl/2
(h)
AUCnorm
M h/mg/kg)
F (%)
(l
25
25a
26a
H
—
A
A
10
24
96
6.3 3.7
1.6 1.7
0.5 0.4
70
c-PrSO2
c-PentSO2
79
nd*
20
22
24
25b
26b
CH3SO2
CH3CH2SO2
i-PrSO2
c-PrSO2
c-PentSO2
B
B
B
B
B
1.1
11
48
5.2 22
1.3 5.6
6.2 47
1.5 0.9
ꢀ100
84
93
1.6
7.0
0.9
ꢀ100
41
nd*
30
31
34
35
37
CH3CH2CONH
c-PrCONH
CH3SO2NH
CH3CH2SO2NH
c-PrSO2NH
C
C
C
C
C
60
64
16
12
24
2.2 0.7
5.5 0.6
2.0 2.5
2.1 3.4
1.5 1.6
nd*
nd*
nd*
nd*
nd*
*
Compounds were tested in mixture PK studies, no F % was measured.
selected for further PK profiling in dog. The results of these studies
are shown in Table 4. Overall, these three analogs displayed excel-
lent pharmacokinetic profiles compared to the non-substituted
analog 2 in rats and dogs.5 The methylsulfonamide 20 exhibited
the longest half-life in rats (11 h) and dogs (22 h). In addition, this
compound was found to be clean of ion channel activity (IC50
>30 l
M at IKr and Cav1.2).5 In a glucose tolerance test (OGTT) in
lean mice, compound 20 displayed comparable glucose lowering
efficacy to sitagliptin and inhibited 85% DPP-4 activity at 0.3 mg/
kg dose in a pharmacodynamic (PD) assay.6
The retention of potency with structurally diverse side-chains
prompted us to examine the X-ray of this class of compounds.
The 2-cyclopropylsulfonamide analog 25b was co-crystallized with
DPP-4 enzyme to obtain an X-ray crystal structure of the ligand–
enzyme complex. 1- and 3-Cyclopropyl sulfonamides 25a and 37
were then selected to model in the DPP-4 enzyme to better
understand the binding mode of the three cyclopropysulfonamide
regioisomers. As shown in the top image of Figure 2, the major
binding interactions of sitagliptin 1 (yellow) and the compound
25b (green) with DPP-4 are conserved. The 2-F atom of the difluo-
rophenyl group interacts with the side chain of R125 via a hydro-
gen bonding. Two additional hydrogen bonds are formed between
the basic amine and E205 and E206.6 The cyclopropylsulfonyl side
chain extends further into the binding cavity than sitagliptin but is
located in an area opened up by the flexible side chain of R358.
The middle image of Figure 2 displays the model analysis of
compound 25a (green) and is superpostitioned with the sitagliptin
1 (yellow) bounded to the DPP-4 enzyme. Similar to 25b, the com-
pound 25a shares the key binding interactions with sitagliptin 1.
The cyclopropylsulfonyl group now faces the solvent cavity and
is easily accommodated in this location.
Figure 2. Top: superposition of sitagliptin 1 and compound 25b bounded in the
DPP-4 enzyme using their X-ray structures (PDB code: 4PNZ). Middle: X-ray crystal
structure of sitagliptin 1 and modeling of compound 25a. Bottom: X-ray crystal
structure of sitagliptin 1 and modeling of compound 37. The images were generated
using Pymol.
The modeling of 3-cyclopropylsulfonamide compound 37
(green) and overlay with sitagliptin 1 (yellow) are shown in the
Table 4
Pharmacokinetic properties of long acting DPP-4 inhibitors in preclinical spices (1 mg/kg iv and 2 mg/kg po)
Compd
R
Species
Clp (ml/min/kg)
t1/2 (h)
AUC (
lM h/mg/kg)
F (%)
IKr IC50 (nM)
>30,000
Cavl.2 IC50 (nM)
>30,000
2
H
Rat
Dog
10
2.7
6.3
13
3.7
16
70
83
20
CH3SO2
C2H5SO2
c-PrSO2
Rat
Dog
1.1
0.9
11
22
48
54
ꢁ100
ꢁ100
84
39,000
>60,000
21,000
>30,000
>30,000
>30,000
22
Rat
Dog
1.6
3.3
5.2
13
22
25
ꢁ100
25b
Rat
Dog
0.9
1.6
6.2
17
47
25
ꢁ100
90
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P. Chen et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
5
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bottom image of Figure 2. A direct overlay of 37 would cause the
3-cyclopropyl sulfonamide group to bump into the enzyme back
wall. Rotation of 37 would then move the cyclopropyl sulfonamide
group into the open area of the solvent cavity with minimal ener-
getic cost. In addition to the similar hydrogen bonding interactions
as compound 1, the sulfonamide group would be further stabilized
by an additional hydrogen bond formed with the side chain of
Y585.
In conclusion, we have prepared a series of novel substituted
dihydropyrrolopyrazole DPP-4 inhibitors. In most cases, they are
potent and highly selective DPP-4 inhibitors with excellent phar-
macokinetic properties and safety profiles. X-ray and modeling
analysis demonstrate that selected analogs retain the key interac-
tions that sitagliptin expresses with the DPP-4 binding pocket.
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study, the methylsulfonamide analog 20 (MK-3102, omarigliptin)6
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Please cite this article in press as: Chen, P.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.10.070