7-Oxopyrrolopyridine-derived DPP4 inhibitors - Mitigation of CYP and hERG liabilities via introduction of polar functionalities in the active site

Article abstract of DOI:10.1016/j.bmcl.2011.09.074

Design, synthesis, and SAR of 7-oxopyrrolopyridine-derived DPP4 inhibitors are described. The preferred stereochemistry of these atropisomeric biaryl analogs has been identified as Sa. Compound (+)-3t, with a K_i against DPP4, DPP8, and DPP9 of 0.37 nM, 2.2, and 5.7 μM, respectively, showed a significant improvement in insulin response after single doses of 3 and 10 μmol/kg in ob/ob mice.

Full text of DOI:10.1016/j.bmcl.2011.09.074

Bioorganic & Medicinal Chemistry Letters 21 (2011) 6646–6651
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
7-Oxopyrrolopyridine-derived DPP4 inhibitors—mitigation of CYP and hERG
liabilities via introduction of polar functionalities in the active site
Wei Wang a, , Pratik Devasthale a, , Aiying Wang b, Tom Harrity b, Don Egan b, Nathan Morgan b,
Michael Cap b, Aberra Fura c, Herbert E. Klei d, Kevin Kish d, Carolyn Weigelt e, Lucy Sun f, Paul Levesque f,
Yi-Xin Li g, Robert Zahler a, Mark S. Kirby b, Lawrence G. Hamann a,
⇑
⇑
a Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, USA
b Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, USA
c Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, USA
d Macromolecular Crystallography, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, USA
e Computer-Assisted Drug Design, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, USA
f Discovery Toxicology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, USA
g Discovery Analytical Sciences, Bristol-Myers Squibb Research and Development, 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:
Received 18 July 2011
Revised 16 September 2011
Accepted 19 September 2011
Available online 24 September 2011
Design, synthesis, and SAR of 7-oxopyrrolopyridine-derived DPP4 inhibitors are described. The preferred
stereochemistry of these atropisomeric biaryl analogs has been identified as Sa. Compound (+)-3t, with a
Ki against DPP4, DPP8, and DPP9 of 0.37 nM, 2.2, and 5.7
ment in insulin response after single doses of 3 and 10
l
l
M, respectively, showed a significant improve-
mol/kg in ob/ob mice.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
DPP4 inhibitors
7-Oxopyrrolopyridines
Atropisomers
Diabetes mellitus
In the past few years, inhibitors of dipeptidyl peptidase 4
(DPP4), a member of the serine protease super-family, have at-
tracted considerable attention as novel therapeutic agents for the
treatment of diabetes mellitus.1 Sitagliptin (Januvia™),2 saxaglip-
tin3 (Onglyza™), vildagliptin (Galvus™),4 and linagliptin (Tradjen-
ta™)5 are approved agents for the treatment of type 2 diabetes, and
alogliptin6 is in advanced stages of clinical trials. While many anti-
diabetic agents cause weight gain in patients and can cause hypo-
glycemia, DPP4 inhibitors have shown weight neutrality and are
associated with a very low incidence of hypoglycemic events. A
considerable amount of effort has thus been focused on the devel-
opment of DPP4 inhibitors as a novel therapy for the treatment of
diabetes.
hERG and CYP liabilities while retaining potency and selectivity.
While the significance of DPP selectivity remains a topic of debate
in the literature, as a secondary goal, we sought to maximize
selectivity for DPP4 versus DPP8/9 in this back-up series to miti-
gate against any potential issues. Monocyclic DPP4 inhibitors such
as 1 have been reported in the literature.8a Based on the X-ray
co-crystal structure8b of a close analog of 1 (not shown) bound to
DPP4 and our internal structural studies7 on cores analogous to
the proposed structures (3–5, A) in Figure 1, we hypothesized that
introduction of nitrogen-containing heterocycles such as 3, 4, 5, or
A, would allow for facile functionalization and variation of R
groups in the solvent-exposed region of the enzyme active site.
The elaboration of series A will be the subject of a separate disclo-
sure from our laboratories.
Synthesis of 7-oxopyrrolopyridine analogs (3) followed a litera-
ture protocol (Scheme 1), whereby benzylidines 7a and 7b were
condensed with methyl or ethyl 3-aminocrotonate to give dihydro-
pyridines, which were further oxidized with nitric acid to 7-oxopyr-
rolopyridine esters 8a and 8b, respectively, in good yield.9 Esters 8a
and 8b were reduced to alcohols 9a and 9b, respectively, with LiBH4,
and then converted to the desired primary amines 3a and 3b by
sequential treatment with mesyl chloride and 7 N NH3/MeOH under
microwave conditions.10
Earlier work from our laboratories had identified potent and
selective DPP4 inhibitors via exploitation of differences in the
solvent-exposed region of the DPP4 and DPP8/9 enzymes.7 Herein,
we describe a continuation of this approach through the discovery
and development of pyrrolopyridines with the goal of mitigating
⇑
Corresponding authors.
E-mail address: pratik.devasthale@bms.com (P. Devasthale).
Current address: Novartis Institutes for Biomedical Research, 250 Massachusetts
Avenue, Cambridge, MA 02139, USA.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.09.074

W. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6646–6651
6647
MeO
Ph
N
NH2
conformational
MeO
N
NH2
NH2
NH2
constraint
Cl
Cl
Ref. 7a
Cl
Cl
1, IC50 = 0.92 µM
2, IC50 = 7 nM
O
N
N
N
N
R N
R N
R N
R N
NH2
Cl
NH2
Cl
NH2
NH2
O
Cl
Cl
Cl
Cl
Cl
Cl
3
4
5
A
(7-oxo-pyrrolopyridine) (pyrrolopyridines) (dihydropyrrolopyridines)(5-oxo-pyrrolopyridine)
Figure 1. Design of pyrrolopyridines.
O
O
O
N
R N
R N
a-c
d, e
CO2R'
Cl
RNH2
Cl
Cl
Cl
7a (R = Bn), 42%
6a (R = Bn)
8a (R = Bn, R' = Et), 68%
7b (R = 4-OMe-Bn), 13%
6b (R = 4-OMe-Bn)
8b (R = 4-OMe-Bn, R' = CH3), 66%
O
O
N
R N
N
f
g, h
R N
NH2
OH
Cl
Cl
Cl
Cl
9a (R = Bn), 34%
3a (R = Bn), 60%
9b (R = 4-OMe-Bn), 72%
3b (R = 4-OMe-Bn), 34%
Scheme 1. Reagents and conditions: (a) ethyl acrylate, EtOH, rt, 15 h; (b) diethyl oxalate, NaOEt, EtOH, reflux, 1 h; (c) 2,4-dichlorobenzaldehyde aq HCl/EtOH, reflux, 4 h; (d)
ethyl 3-aminocrotonate, HOAc, reflux, 1.5 h; (e) 1 N HNO3, reflux, 30 min; (f) LiBH4, THF, cat MeOH, rt, 15 h; (g) MsCl, Et3N, DCM, rt, 2 h; (h) 7 N NH3 in MeOH, microwave,
100 °C, 5 min.
N
N
N
N
NH2
d,a,b,c
9%
a,b,c
17%
NH2
8a
Cl
Cl
Cl
Cl
4a
5a
Scheme 2. Reagents and conditions: (a) LAH, THF, 0 °C to rt, 20 min; (b) MsCl, Et3N, DCM, rt, 3 h; (c) 7 N NH3 in MeOH, microwave, 100 °C, 15 min; (d) DIBAL-H, THF, rt, 3 h.
Synthesis of pyrrolopyridine 4a and dihydropyrrolopyridine 5a
(Scheme 2), was low-yielding but expedient. LAH reduction of
intermediate 8a to the corresponding dihydropyrrolopyridine
followed by the 2-step treatment with MsCl and NH3/MeOH affor-
ded primary amine 5a, whereas use of a milder reducing agent (DI-
BAL) afforded the pyrrole intermediate with the ester moiety
intact. Subsequent treatment with LAH reduced the ester to the
alcohol, which was then transformed to pyrrolopyridine 4a follow-
ing the usual sequence in 9% overall yield.
SAR elaboration. All three compounds showed moderately potent
DPP4 inhibition, and hence could serve as good starting points
(Table 1). Compound 4a was chemically unstable and hence was
not progressed further.
Due to compound 3a’s relatively superior PK properties and CYP
profile, 7-oxo-pyrrolopyridine was chosen over 5a as the bicyclic
core for SAR optimization, despite 5a’s apparent higher peptidase
selectivity. All three compounds displayed CYP3A4, hERG and
PXR liabilities.
We initially sought to identify the most suitable of the three
bicyclic cores, represented by compounds 3a, 4a, and 5a, for further
We began by exploring aryl substituents on the lactam nitrogen,
taking advantage of Chan-Lam’s versatile copper-mediated N-aryla-

6648
W. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6646–6651
tion methodology (Scheme 3).11 N-Arylations of Boc-protected
Table 1
Activity and liability profiles of 3a, 4a, and 5a
lactam10 followedby deprotectionof thecoupled productsafforded
compounds 3 (Route A). Aryl boronic acids with either electron-
withdrawing or ortho-substituents on the phenyl group did not cou-
ple well with lactam 10, yielding only trace amounts of the desired
products. In these cases (such as 3f, 3h, and 3l), acceptable yields
of coupled products were obtained from lactam-ester 11 (Route B).
Subsequent transformations of the esters (12) to primary amines 3
were carried out in the usual manner in modest yields.
The unsubstituted phenyl analog (3c), with a Ki against DPP4 of
8 nM, displayed approximately 500-fold selectivity versus DPP8/9,
but also suffered from potent hERG channel (69% inhibition at
10 lM) and CYP3A4 inhibitory activities (Table 2). Exploring
o-, m-, and p-methoxy substitution (3f, 3e, 3d) suggested that
3a
4a
5a
DPP4 Ki
DPP8 Ki
DPP9 Ki
30
29
51.5
3164
8511
15
2.8/1.4
72
4254
5860
0.95
>30,000
>30,000
0.34
0.77/0.34
67
CYP 2C19, IC50
(
l
M)
M)
Mb
CYP 3A4a IC50
(l
1.1/0.73
,
hERG%inhib @ 10
l
NDc
PXR, EC20/60
(l
M)
0.47/1.4
500
1.9/>5.6
ND
1.1/3.3
76
d
Cmax (nM)
a
IC50s versus substrates 7-benzyloxy-4-trifluoromethyl coumarin/7-benzyloxy
resorufin.
b
Patch clamp assay.
hERG flux assay, IC50 = 14
Coarse rat PK study with a 10
c
l
M.
d
l
mol/kg dose.
o-substitution was most favored for DPP4 potency, with compound
O
O
N
N
N
Route A
a-e
HN
f,g
NHR'
NH2
X
8b
Cl
Cl
12-48%
22%
3
Cl
Cl
10 (R' = Boc)
e
c
-
Route B
g
a
%
70%
8
4
96%
-
3m (R' = H)
5
3
O
O
N
N
N
h
HN
CO2CH3
Cl
CO2CH3
Cl
X
25-46%
Cl
12 Cl
11
Scheme 3. Reagents and conditions: (a) LiBH4, THF, cat MeOH, rt, 6–48 h; (b) MsCl, Et3N, DCM, rt, 4–12 h; (c) 7 N NH3/MeOH, microwave, 100 °C, 5–15 min; (d) (Boc)2O, aq
NaHCO3, THF, H2O, rt, 12 h; (e) ceric ammonium nitrate, CH3CN, H2O, rt, 6–12 h; (f) aryl boronic acid, Cu(OAc)2, Et3N, py, DCE at 75 °C, 2–12 h; (g) TFA, DCM, rt, 1.5–3 h; (h)
aryl boronic acid, Cu(OAc)2, Et3N, py, DCM, rt, 15 h.
Table 2
In vitro binding activity of 3 against DPP4 isozymes, CYP3A4, and hERG
BMS#
R
Ki (nm)
DPP8
hERG %inhib @ 10
l
Mc
CYP 3A4d
(lM)
DPP4
DPP9
or
b
3ca
Ph
8
4504
688
1708
1518
13,070
886
1084
1039
1174
3820
675
1244
>30,000
>30,000
2282
3999
>30,000
3921
3840
971
69
67
ND
68
67
63
84
ND
82
92
97
ND
68
18
56
ND
ND
À0.1
À1.0
29
1.2
2.5
ND
2.2
1.3
1.5
0.27
ND
0.39
1.4
0.67
ND
>40
>40
17
3da
3ea
3fb
4-OCH3-Ph
3-OCH3-Ph
2-OCH3-Ph
2-OCH3-Ph
2-OCH3-Ph
4-CH3-Ph
2-CH3-Ph
4-Cl-Ph
11
16
3e
36
3
12
9
18
9
2637
1844
13,250
1097
1461
2938
2233
2313
1057
2298
>30,000
ND
(R)-(À)-3f
(S)-(+)-3f
3ga
3hb
3ia
3ja
4-F-Ph
3ka
4-CN-Ph
2-SCH3-Ph
H
4
3lb
12
14
29
3
2.7
76
4
3m
3n
3o
CH3
CH2CO2CH3
CH2CO2CH3
CH2CO2CH3
CH2CO2H
CH2CH2OH
CH2CH2OCH3
ND
(S)-3o
(R)-3o
3p
3439
>30,000
2830
>30,000
>30,000
ND
ND
>40
>40
22
3q
3r
9
4
>30,000
15,960
a
b
c
Prepared by using route A in Scheme 3.
Prepared by using route B in Scheme 3.
hERG patch clamp assay.
IC50s against 7-benzyloxy-4-trifluoromethyl coumarin.
Non-competitive ND = not determined.
d
e

W. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6646–6651
6649
O
N
O
O
N
N
N
N
N
Chiral HPLC
OJ column
NH2
NH2
NH2
OCH3
+
OCH3
Cl
Cl
OCH3
Cl
Cl
Cl
Cl
(-)-3f
DPP4 Ki = 36 nM
(+)-3f
rac-3f
DPP4 Ki = 3 nM
DPP4 Ki = 3 nM
Scheme 4. Chiral separation of rac-3f: Chiralcel OJ column, 85%Heptane/7.5%EtOH/7.5% MeOH + 0.1% DEA.
3f approximately 2- to 3-fold more potent at DPP4, DPP8, and DPP9
relative to 3c. Moreover, compound 3d (R = 4-MeO-Ph) had signifi-
cantly reduced selectivity versus DPP8 and DPP9 (63- and 88-fold,
respectively) relative to 3c. This was a trend observed for all other
4-substituted analogs as well (3g–3k). Substitution on the phenyl
group failed to mitigate the significant CYP3A4 and hERG liabilities.
Compounds 3 exist as mixtures of non-interconvertible atropi-
somers due to restricted rotation around the biphenyl linkage. In
order to further assess the absolute stereochemical preference in
binding to DPP4, individual atropisomers (+)-3f and (À)-3f were
isolated via chiral HPLC separation. The assignment of stereochem-
istry of (+)-3f and (À)-3f was based on X-ray crystallographic anal-
ysis of the slower-moving atropisomer (+)-3f bound to DPP4 (Fig. 2).
The X-ray analysis suggests that the dichlorophenyl group is
nearly orthogonal to the bicyclic ring system with the proximal Cl
group oriented below the plane of the paper as depicted in Scheme
4. Two orientations of the 2-MeO-Ph group (shown in magenta and
sage colors), with roughly equal occupancies, were observed. This
group, which does not have any significant interactions in the active
site, is predominantly exposed to solvent except for a pi-stacking
interaction which appears to exist between the 2-methoxyphenyl
group in (+)-3f and Tyr547 with an interplanar distance of approx-
Figure 2. X-ray co-crystal structure of (+)-3f (magenta and sage green) bound to
DPP4 showed the Sa atropisomer to be the active form. Independent of stereo-
isomerism, the 2-methoxy phenyl group was observed in two conformations (PDB
entry: 3SX4).
O
O
N
O
N
N
a
b
N
c,d
N
N
NHR
NHBoc
10 80%O
4%
NH2
OH
52%
OCH3
OCH3
Cl
Cl
Cl
Cl
Cl
Cl
13
14 (R' = Boc)
3q (R' =H)
3r
d
25%
d,e
32 %
O
O
N
N
N
N
NH2
Cl
NH2
H3CO
H3CO
O
O
Cl
+
Cl
Cl
(R)-3o
(S)-3o
O
N
O
N
N
R1
f
g, h,d
N
NH2
NHBoc
(S) -3o
N
H3CO
R2
O
O
Cl
> 95%
Cl
> 50%
Cl
Cl
(S) -13
3s-3dd
Scheme 5. Reagents and conditions: (a) BrCH2CO2Me, NaH, DMF, rt, 3 h; (b) LiBH4, THF, rt, 4 h; (c) Ag2O, MeI, CH3CN, rt, 3 d; (d) TFA, DCM, rt, 3 h; (e) Chiralcel OJ column,
85%Heptane/7.5%EtOH/7.5% MeOH + 0.1% DEA; (f) (Boc)2O, aq NaHCO3,THF, temp, 2 h; (g) LiOH, THF–H2O (v:v = 1.5:1), rt, 3 h; (h) R1R2NH, PyBOP, DIEA, THF, rt, 5 h.

6650
W. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6646–6651
Table 3
137%
Amide analogs
60
95%
(+)-3t
P < 0.02
*
R
Ki (nM)
68%
50
(+)-3t
*
DPP4
DPP8
DPP9
BMS-538305
40
30
20
10
0
*
(+)-3s
(+)-3t
(+)-3u
(+)-3v
CH2CONH2
CH2CONHCH3
CH2CON(CH3)2
CH2CON(Et)2
O
1.5
3701
2238
2688
823
10,490
5771
3496
2340
0.37
0.27
0.43
N
CONH2
(+)-3w
(+)-3x
0.29
0.55
3477
993
5982
1536
Vehicle
3 µmol/kg
3 µmol/kg
10 µmol/kg
O
N
Figure 4. Insulin responses for compound (+)-3t in an acute OGTT study in ob/ob
mice.1C57BL/6J-ob/ob mice on
group = 10–12.
a
4-week high-fat diet. 2Number of mice per
NCOCH3
O
N
NSO2CH3
NCH3
(+)-3y
0.46
0.67
0.30
0.31
0.40
3106
1894
802
967
60
1101
>10,000
1890
2430
262
in the series as we attempted to mitigate liabilities. However, intro-
duction of a variety of substitutions on the phenyl ring had minimal
impact on liabilities. Fortuitiously, the unsubstituted lactam (3m),
possessed potent DPP4 inhibitory activity (Ki = 14 nM) with signifi-
cantly improved selectivity (>2000-fold) versus DPP8 and DPP9.
Moreover, 3m was devoid of CYP3A4 inhibitory activity up to
O
N
(+)-3z
O
N
(+)-3aa
(+)-3bb
(+)-3cc
40 lM. Thus, development of SAR around aliphatic substituents
O
N
on the lactam nitrogen, with a focus on optimizing DPP4 activity
and retaining the lack of CYP inhibitory activity, was undertaken.
N-Alkylation of unsubstituted lactam 10 with methyl bromo
acetate gave methyl ester 13 in good yield (Scheme 5). Reduction
of 13 followed by Boc deprotection gave 2-hydroxyethyl analog
3q. The N-methyl analog 3n was prepared in an analogous manner
via alkylation with MeI. The methoxyethyl analog 3r was obtained
by methylation of the primary alcohol 14 in the presence of Ag2O
in low yield followed by deprotection of the Boc group. Amides
3s–3dd were prepared as single atropisomers via separation of es-
ter intermediate 3o using chiral HPLC and carrying forward the
more active ester isomer (S)-3o through usual functional group
manipulations.14
O
O
N
N
H
N
N
O
(+)-3dd
0.26
558
1710
NH
Introduction of alkyl functionalities on the lactam nitrogen, as
in analogs 3o–3r, resulted in DPP4 inhibition in the single-digit
nanomolar range (Tables 2 and 3). Additionally, these analogs
showed >700-fold selectivity over DPP8 and DPP9 and significantly
reduced CYP3A4 (IC50 >17
lM for all analogs in Table 3, except (+)-
3dd with an IC50 of 7 M) and hERG liabilities (IC50 >80
l
lM). Incor-
poration of polar functionality, such as in carboxylic acid (3p) and
primary alcohol (3q) likely contributed to the mitigation of CYP/
hERG liabilities. The wide range of moieties tolerated in this region
of the DPP4 active site is consistent with the X-ray data wherein
these groups point toward solvent. Most amides were nearly an
order of magnitude more potent than the precursor acid (3p). With
the exception of 3dd, they also retained the favorable CYP3A4
liability profile of 3p, as well as high selectivity versus DPP8 and
DPP9. These analogs also showed minimal activity in the in vitro
PXR assays (data not shown). For example, PXR EC20/60 for com-
pound (+)-3t was >50 lM.
Figure 3. X-ray co-crystal structure of 3r (magenta) bound to DPP4 (PDB entry:
In order to better understand the improved selectivity of N-ali-
phatic analogs for DPP4 over DPP8/9 compared to N-aromatic ana-
logs, homology models of DPP8 and DPP9 with (+)-3f and 3r docked
in the active site were generated using PRIME (version 2.0, Schro-
dinger, LLC, New York, NY). For both classes of analogs, most of
the binding interactions in DPP4 are also present in DPP8/9. A pi-
stacking interaction between Tyr547 and the 2-methoxyphenyl of
(+)-3f is seen in the DPP4 crystal structure (RCSB entry 3SX4) and
DPP8/9 homology models. No direct interaction of the methoxy-
ethyl moeity of 3r and protein in the DDP4 crystal structure
(Fig. 3, RCSB entry 3SWW) and DDP8/9 homology models was
noted except for a possible water-mediated interaction to the
side-chains of Arg125 in DPP4, Lys174 in DPP8, and Arg163 in
DPP9. It is conceivable that, due to subtle differences between
3SWW).
imately 3.5 Å.12 (Sa)-(+)-3f was over an order of magnitude more
potent at DPP4, DPP8, and DPP9 than (Ra)-(À)-3f (Table 2). Given
the above X-ray and biological activity data of (Sa)-(+)-3f, coupled
with X-ray crystallographic data from other close analogs gener-
ated internally,13 it was reasonable to assume that the orientation
of the dichlorophenyl group in the more active atropisomer of all
analogs shown in Table 2 would be in the same direction as
depicted for (Sa)-(+)-3f in Scheme 4. Both atropisomers of 3f
showed similarly potent inhibition of hERG and CYP3A4.
The oral bioavailability of 3c in rats was found to be 78%
(t1/2 = 4.4 h), providing additional impetus to further optimize with-

W. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6646–6651
6651
D. M.; Marcinkeviciene, J.; Chang, S. Y.; Biller, S. A.; Kirby, M. S.; Parker, R. A.;
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otype with Tyr547 in DPP8/9 may play a more significant role to-
ward binding affinity relative to DPP4. This would result in
increased affinity of N-aryl lactams toward DPP8/9 relative to N-ali-
phatic lactams, and hence reduced DPP4 versus DPP8/9 selectivity.
Based on a favorable activity and liability profile, compound (+)-
3t was selected to advance to an acute pharmacodynamic study. In
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a rat PK study at 10 lmol/kg po, compound (+)-3t reached a Cmax of
32 nM at a tmax of 25 min.
Despite poor systemic exposure, when administered orally to
7. (a) Brigance, R. P.; Meng, W.; Fura, A.; Harrity, T.; Wang, A.; Zahler, R.; Kirby, M.
S.; Hamann, L. G. Bioorg. Med. Chem. Lett. 2010, 20, 4395; (b) Meng, W.;
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P.; Tamura, J. K.; Xie, D.; Zhang, Y.; Klei, H. E.; Weigelt, C. A.; Tuerdi, H.; Wang,
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M.; Hennig, M.; Kuhn, B.; Loeffler, B.-M. Bioorg. Med. Chem. Lett. 2004, 14, 1491.
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Madhav, R. Synthesis 1973, 609.
ob/ob mice at 3 and 10 lmol/kg (Fig. 4, for study protocol details,
see Ref. 7b), compound (+)-3t induced mean plasma insulin in-
creases of 95% and 137%, respectively. The extent of the increase
at 3
538305.15
A novel series of 7-oxopyrrolopyridine analogs was identified,
lmol/kg was comparable to an internal standard, BMS-
with several compounds showing sub-nanomolar DPP4 inhibitory
potencies and >1000-fold selectivity versus DPP8 and DPP9.
Through extensive SAR work in a solvent-exposed region, hERG
and CYP3A4 liabilities were successfully addressed. Amide analog
(+)-3t displayed efficacy comparable to a potent internal standard,
BMS-538305, in an acute OGTT study in ob/ob mice. As a result of
poorer systemic exposures and development profiles relative to
other more promising series in our program, further work on the
7-oxopyrrolopyridines was discontinued.
10. Saulnier, M. G.; Zimmermann, K.; Struzynski, C. P.; Sang, X.; Velaparthi, U.;
Wittman, M.; Frennesson, D. B. Tetrahedron Lett. 2004, 45, 397.
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3091; (b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan,
D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941.
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1210.
13. X-ray analysis of (Sa)-3o: PDB entry 3Q0T; For a discussion of atropisomerism
in a related series, see: 13 O’Connor, S. P.; Wang, Y.; Simpkins, L. M.; Brigance,
R. P.; Meng, W.; Wang, A.; Kirby, M. S.; Weigelt, C. A.; Hamann, L. G. Bioorg.
Med. Chem. Lett. 2010, 20, 6273.
14. Compound (+)-3t was derived directly from ester (S)-13 (Scheme 5) as
described below:
References and notes
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A mixture of 25 mg of (S)-(+)-13 in 0.6 mL MeOH and methyl amine aqueous
solution (40%, 0.4 mL) in a sealed tube was irradiated in a microwave reactor at
100 °C for 15 min. The methyl amide product obtained was then treated with
TFA/CH2Cl2 (v:v = 3:7) to give (+)-3t in 66% overall yield.
15. Simpkins, L. M.; Bolton, S.; Pi, Z.; Sutton, J. C.; Kwon, C.; Zhao, G.; Magnin, D. R.;
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