Discovery and structure - Activity relationships of piperidinone- and piperidine-constrained phenethylamines as novel, potent, and selective dipeptidyl peptidase IV inhibitors

Article abstract of DOI:10.1021/jm061436d

Dipeptidyl peptidase IV (DPP4) inhibitors are emerging as a new class of therapeutic agents for the treatment of type 2 diabetes. They exert their beneficial effects by increasing the levels of active glucagon-like peptide-1 and glucose-dependent insulino

Full text of DOI:10.1021/jm061436d

J. Med. Chem. 2007, 50, 1983-1987
1983
Discovery and Structure-Activity Relationships of Piperidinone- and Piperidine-Constrained
Phenethylamines as Novel, Potent, and Selective Dipeptidyl Peptidase IV Inhibitors
Zhonghua Pei,* Xiaofeng Li, Thomas W. von Geldern, Kenton Longenecker, Daisy Pireh, Kent D. Stewart, Bradley J. Backes,
Chunqiu Lai, Thomas H. Lubben, Stephen J. Ballaron, David W. A. Beno, Anita J. Kempf-Grote, Hing L. Sham, and
James M. Trevillyan
Metabolic Disease Research, Global Pharmaceutical Research and DeVelopment, Abbott Laboratories,
100 Abbott Park Road, Abbott Park, IL 60064-3500
ReceiVed December 15, 2006
Dipeptidyl peptidase IV (DPP4) inhibitors are emerging as a new class of therapeutic agents for the treatment
of type 2 diabetes. They exert their beneficial effects by increasing the levels of active glucagon-like peptide-1
and glucose-dependent insulinotropic peptide, which are two important incretins for glucose homeostasis.
Starting from a high-throughput screening hit, we were able to identify a series of piperidinone- and piperidine-
constrained phenethylamines as novel DPP4 inhibitors. Optimized compounds are potent, selective, and
have good pharmacokinetic profiles.
Chart 1. DPP4 Inhibitors
Type 2 diabetes is a rapidly growing disease that affects
millions of people worldwide. For instance, 20.8 million children
and adults in the United States alone, or 7% of the population,
have diabetes. The death toll and economic costs associated with
diabetes and its complications are enormously high.1 Recently
dipeptidyl peptidase IV (DPP4,a EC 3.4.14.5) inhibitors have
emerged as a new class of therapeutic agents for treating
diabetes, as evidenced by the FDA approval of 1 (sitagliptin,
Chart 1) as a monotherapy or in combination with other
antidiabetic agents.2,3 Several other DPP4 inhibitors such as 2
(vildagliptin),4 3 (saxagliptin),5 4 (SYR-322),6 and 5 (ABT-279)7
are either awaiting regulatory approval or are in human clinical
trials (Chart 1). Compared to other existing antidiabetic agents,
DPP4 inhibitors have the advantage of (1) not causing hypogly-
cemic episodes; (2) not causing body-weight gain; and (3)
potentially altering disease progression by restoring â-cell
function of the pancreas.8
Chart 2
It is generally accepted that DPP4 inhibitors exert their
beneficial effects by increasing the levels of active glucagon-
like peptide-1 (GLP-1) and glucose-dependent insulinotropic
peptide (GIP). After ingestion of nutrients, GLP-1 and GIP are
released (from L-cells and K-cells, respectively) and then
function through their respective receptors. Specifically, GLP-1
stimulates insulin secretion,9 inhibits glucagon secretion,9c,10 and
delays gastric emptying,11 each a benefit in controlling blood
glucose. GIP has a similar insulinotropic effect but does not
inhibit glucagon secretion or influence gastric emptying in
humans.12,13 However, active GLP-1 (7-36) and GIP (1-42)
are inactivated by DPP4 rapidly by cleavage of two amino acid
residues from the N-terminus.14 Inhibition of DPP4 restores
active GLP-1 and GIP levels and improves glycemic control
for diabetics.
After the successful identification of our first DPP4 inhibitor,
clinical candidate 5 at Abbott,7 our attention focused on the
discovery of noncyanopyrrolidine DPP4 inhibitors. Starting with
the high-throughput screening (HTS) hit 6 (Chart 2), we were
able to identify cyclohexene-constrained phenethylamine 7
(ABT-341) as a backup clinical development candidate.15 Lead-
hopping efforts from the same HTS lead led to a series of
pyrrolidine-constrained phenethylamines as novel and potent
DPP4 inhibitors.16 Herein we report the discovery and structure-
activity relationship (SAR) of a series of piperidinone- and
piperidine-constrained phenethylamines as novel and potent
DPP4 inhibitors.
During the optimization of the cyclohexene-constrained
phenethylamine series, we envisioned that a lactam such as 8
might be a good target to pursue. This core motif offers several
attributes compared to cyclohexene: (1) the amide moiety might
be a good mimetic of the double bond to provide similar rigidity
and trajectory for the required appendages off the central ring;
(2) the nitrogen atom would provide a position for easier
introduction of different substituents para to the aromatic ring.
The synthesis of racemic piperidinone-constrained phenethy-
lamines is outlined in Scheme 1. R,â-Unsaturated esters 9 or
10 underwent Michael addition with nitromethane to give γ-nitro
esters 11 or 12 under basic conditions. A three-component
cyclization17 involving nitro ester 11 or 12, paraformaldehyde,
and amines afforded lactams 13 or 14 as the major isomers,
* To whom correspondence should be addressed. Tel.: (847) 935-6254.
Fax: (847) 937-1674. Email: zhonghua.pei@abbott.com.
a Abbreviations: DPP4, dipeptidyl peptidase IV; GLP-1, glucagon-like
peptide-1; GIP, glucose-dependent insulinotropic polypeptide; HTS, high-
throughput screening.
10.1021/jm061436d CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/17/2007

1984 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8
Brief Articles
Scheme 1a
Table 1. Inhibition Constant (Ki) of Piperidinone-Constrained
Phenethylaminesa
a Reagents and conditions: (a) CH3NO2, DBU; (b) paraformaldehyde,
RNH2, ethanol, 90 °C; (c) Zn, HOAc, MeOH, 75 °C; (d) cat. CuI, N,N’-
dimethylethylenediamine, iodobenzene, toluene, 110 °C.
Scheme 2a
a Reagents and conditions: (a) diethyl malonate, N-methylmorpholine,
cat. Mg(OTf)2, ligand 27, 4 Å mol. sieves, CHCl3; (b) paraformaldehyde,
RNH2, ethanol, 85 °C; (c) NaCl, DMSO/H2O, 140 °C; (d) Zn, HOAc,
MeOH, 75 °C.
wherein with the nitro and aromatic groups trans to each other.
This cyclization failed when aniline was used (R ) Ph)
presumably due to insufficient nucleophilicity of the anilinic
nitrogen. The phenyl group was introduced by using a Buchwald
condition of Goldberg coupling between iodobenzene and 13a
to give 15 in low yield.18 Reduction of the nitro group of 13-
15 provided aminolactams 16-25.
Synthesis of optically pure piperidinone-constrained phen-
ethylamines was accomplished by a methodology developed in
these laboratories (Scheme 2).19 Asymmetric Michael addition20
of the malonate anion to nitrostyrene 26 catalyzed by the
complex of magnesium triflate and the C2-symmetric bisox-
azoline ligand 27 provided 1,3-diester 28 in R-configuration as
shown in >95% ee, as determined by chiral HPLC.21 The critical
three-component cyclization of dicarbonyl 28, paraformalde-
hyde, and amines efficiently yielded lactams 29. Decarboxyla-
tion was achieved under neutral conditions at 140 °C22 to give
lactams 30, which were converted to amines 31-35 by reduction
of the nitro group with zinc.
Inhibitory potency of the synthesized compounds was mea-
sured by monitoring the hydrolytic reaction of Gly-Pro-7-amido-
methylcoumarin (Gly-Pro-AMC) by human DPP4, and the
results are reported as inhibitory constants (Ki).23 Piperidinone
16 with a phenyl group directly attached to the ring nitrogen
atom was a weak inhibitor with a Ki of 1.6 µM (Table 1).
Replacement of the phenyl with a benzyl group led to 17 with
Ki of 1.4 µM. Analogue 18, with a saturated cyclohexyl ring,
did not possess significantly improved potency (Ki ) 0.93 µM).
When the aromatic group was switched from 2-chlorophenyl
to 2,4,5-trifluorophenyl, a group that was used by others2 and
us in other series,15,16 the resulting amine 19 was about 3-fold
more potent (Ki ) 0.44 µM) than 17. A dramatic improvement
a Values reported are the mean of at least two runs using human DPP4.
b A ) 2-chlorophenyl; B ) 2,4,5-trifluorophenyl. c Racemic. d Diastereo-
meric mixture of racemic core and (S)-2-phenylpropan-1-amine. e Enan-
tiomerically pure. f The enantiomer of compound 31.
came when the N-benzyl was extended to a phenethyl. The
resulting analogue 20 showed a 25-fold improved potency over
19, achieving a Ki of 17 nM. When the linker was extended
further to three carbons, the potency of the resulting analog 21
suffered (Ki ) 270 nM). Within the two-carbon linker series, a
methyl group on the linker (22) caused an approximate 5-fold
loss of potency compared to that of 20. When the phenyl ring
was replaced with a morpholinyl ring, the potency (23)
decreased significantly (Ki ) 590 nM). When the phenyl group
was replaced with a pyridinyl group, the corresponding analogue
24 showed approximately the same potency (24 nM) as the
phenyl analogue. Introduction of the methylenedioxyphenyl
group provided racemic 25 with an improved Ki of 7.1 nM.
When this analogue was prepared in optically pure form, the
corresponding amine 31 had a Ki of roughly half of that of 25,
3.2 nM. The corresponding enantiomer 32 was much less potent,
with a Ki of 105 nM, demonstrating the importance of the
absolute stereochemistry. Analogue 33, with a methylsulfonyl
group at the para-position, had a Ki of 12 nM. When the
methylsulfonyl group was moved to the meta-position, the
resulting analogue 34 exhibited improved potency (4 nM) and
good PK (vide infra). Analogue 35, with an ionizable carboxy-
late group, was also very potent (3.8 nM).

Brief Articles
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8 1985
Scheme 3a
Table 2. Inhibition Constant (Ki) of Piperidine-Constrained
Phenethylaminesa
a Reagents and conditions: (a) BH3, THF (b) Zn, HOAc, MeOH, ∆; (c)
Boc2O, CH2Cl2/THF; (d) Pd/C, HCO2NH4, MeOH, ∆; (e) PhNCO, TEA,
CH2Cl2; (f) TFA, CH2Cl2; (g) 4,6-dichloropyrimidine, 100 °C or 2,4-
dichloro-1,3,5-triazine, i-Pr2NEt, -40 to -5 °C; (h) ArB(OH)2, cat.
Pd(PPh3)4, Na2CO3, toluene/EtOH/H2O, 90 °C for 41-43; or NHR1R2,
145-160 °C, microwave for 44-49.
Because it was unclear whether the lactam carbonyl group
interacts with DPP4, piperidine-constrained phenethylamines
were prepared (Scheme 3). A series of structurally related
aminopiperidines, which were synthesized via a different route,
were recently patented.24 After the carbonyl group of optically
pure lactam 30 (R ) Bn) was selectively reduced by borane,
the nitro group was reduced to the corresponding amine group,
which was then protected by a tert-butoxycarbonyl (Boc) group
to provide 36. Removal of the N-benzyl group by catalytic
hydrogen transfer provided the key intermediate, piperidine 37.
Reaction of piperidine 37 with phenylisocyanate and subsequent
removal of the Boc group gave urea 38. Alternatively, a
nucleophilic substitution reaction between piperidine 37 and 4,6-
dichloropyrimidine or 2,6-dichlorotriazine gave chlorides 39 or
40. A Suzuki coupling between chloride 39 or 40 and boronic
acids followed by removal of the Boc group gave amines 41-
43. A nucleophilic substitution reaction between chloride 39
and different amines at elevated temperatures and subsequent
removal of the Boc group gave amines 44-49.
Structure-activity relationships of the piperidine-constrained
phenethylamines are summarized in Table 2. Piperidine 38, with
a urea linker between the phenyl group and the core lactam,
was reasonably potent, with a Ki of 140 nM. Replacement of
the open-chain linker with a more rigid pyrimidine dramatically
improved the potency of the resulting analogue 41 (Ki ) 6.1
nM). Unlike the pyrrolidine-constrained phenethylamine series,
where the introduction of a methylsulfonyl group improved
potency significantly,16 introduction of a methylsulfonyl group
here (42) changed the potency very little (Ki ) 4 nM). Again
unlike the pyrrolidine-constrained phenethylamine series, where
the triazine analogues are more potent than the corresponding
pyridimine agalogues, triazine sulfone 43 was less potent than
the corresponding pyrimidine sulfone 42, demonstrating the
subtle difference between these two series. When the aromatic
group was replaced with a nonaromatic pyrrolidinyl group, the
resulting analogue 44 had a Ki of 2.3 nM. When the five-
membered pyrrolidinyl group was replaced with a six-membered
a Values reported are the mean of at least two runs using human DPP4.
Table 3. Selectivity of Selected Inhibitorsa
compd
DPP4
DPP8
DPP9
31
34
35
42
47
48
3.2
4.0
3.8
4.0
1.6
2.3
>3000
>3000
>3000
>30 000
19 100
>3000
>3000
>3000
>30 000
18 300
19 700
>30 000
a All are Ki values in nM. For structures, see Tables 1 and 2.
piperdinyl group (45), the potency decreased (Ki ) 11 nM).
When the pyrrolidine ring was replaced by an open-chain
diethylamine group, the resulting analogue 46 was 10-fold less
potent than 44. Difluoro substitution on the pyrrolidinyl ring
provided the most potent analogue 47, with a Ki of 1.6 nM.
Both a polar hydroxyl group on the pyrrolidinyl ring (48) and
a bicyclic heteroaromatic ring (49) were well tolerated, providing
very potent inhibitors.
Potent inhibitors were tested against a panel of related
peptidases, including FAPR, POP, DPP7, DPP8, and DPP9.
Selectivity against DPP8/9 is of particular importance because
inhibition of DPP8/9 has been associated with toxicity in animal
studies.25 Our piperidinone- and piperidine-constrained phen-
ethylamines are generally highly selective for DPP4 over the
related dipeptidyl peptidases FAPR, POP, DPP7 (data not
shown), DPP8, and DPP9 (data shown in Table 3). As can be
seen, all the compounds show at least ∼1000-fold selectivity
over these two enzymes.
X-ray crystal structures of the complexes of inhibitors 31 and
42 bound to human DPP4 reveal several interesting features
(Figure 1).26 The general orientation of the two inhibitors is
very similar. The trifluorophenyl group occupies the S1 pocket

1986 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8
Brief Articles
Experimental Section
The synthesis of 42 (last three steps) is illustrated below. For
complete experimental details of the synthesis of all intermediates
and final products, see Supporting Information.
tert-Butyl (3R,4R)-1-(6-Chloropyrimidin-4-yl)-4-(2,4,5-trifluo-
rophenyl)piperidin-3-ylcarbamate (39). Piperidine 37 (1.21 g,
3.66 mmol, 1 equiv), 4,6-dichloropyrimidine (0.655 g, 1.2 equiv),
and i-PrNEt2 (0.96 mL, 1.5 equiv) were mixed in i-PrOH (12 mL).
The mixture was heated to 100 °C and stirred for 1.3 h. After the
reaction was cooled to rt, saturated aq NaHCO3 solution was added,
and the mixture was extracted with EtOAc (3 × 30 mL). The
combined organic extract was dried (Na2SO4) and concentrated.
The resulting residue was purified using an Analogix flash
chromatographer (13% then 22% EtOAc/Hex) to give the desired
product as a white solid (1.5 g, 86%). 1H NMR (300 MHz, CDCl3)
δ ppm 8.42 (s, 1H), 6.99-7.15 (m, 1H), 6.86-7.00 (m, 1H), 6.63
(s, 1H), 4.50-4.75 (m, 1H), 4.29-4.46 (m, 1H), 3.62-3.82 (m,
1H), 2.87-3.11 (m, 2H), 2.81 (t, J ) 11.9 Hz, 1H), 1.98 (d, J )
10.8 Hz, 1H), 1.61-1.85 (m, 2H), 1.35 (s, 9H). MS (ESI) m/z 443
and 445 (M + H)+.
Figure 1. X-ray crystal structures of inhibitors 31 (green) and 42
(brown) complexed to huDPP4. Color-coding: all nitrogen atoms are
in blue, oxygen atoms are in red, and fluorine atoms are in cyan. The
carbon atoms of DPP4 are in gray.
Table 4. Pharmacokinetic Properties of Selected Compoundsa
CLp
Vss
Cmax
t1/2
AUC
F
compd
(L/hr‚kg)
(L/kg)
(ng/mL)
(h)
(ng‚hr/kg)
(%)
(3R,4R)-1-(6-(3-(Methylsulfonyl)phenyl)pyrimidin-4-yl)-4-
(2,4,5-trifluorophenyl)piperidin-3-amine (42). Chloride 39 (1.10
g, 2.48 mmol, 1 equiv), 3-methylsulfonylphenyl boronic acid (0.62
g, 6.20 mmol, 1.25 equiv), Pd(PPh3)4 (0.287 g, 0.248 mmol, 0.1
equiv), and Na2CO3 (0.657 g, 6.2 mmol, 2.5 equiv) were mixed in
toluene/EtOH/H2O (3.2:3.2:1.0 mL). The mixture was then heated
to 90 °C under argon. After 2 h, additional Pd(PPh3)4 (100 mg)
and dioxane (4 mL) were added. After about 3 h, the reaction was
cooled to rt and water was added. The mixture was extracted with
Et2O/EtOAc (3×). The combined organic extract was dried (Na2-
SO4) and concentrated. The resulting residue was purified using
an Analogix flash chromatographer (40% then 65% EtOAc/hexane)
to give the desired product as a yellow solid (1.29 g, 93%).
The above sulfone (1.27 g, 2.26 mmol) was treated with
precooled (0 °C) 4 N HCl in dioxane (6 mL). The mixture was
stirred at rt for 2 h, and then MeOH (7 mL) was added to dissolve
the precipitate. This homogeneous solution was then added slowly
to stirred ether (220 mL) in a separate flask. The resulting precipitate
was collected by filtration and dried in vacuo to give the desired
product as a HCl salt (1.02 g, 95%). 1H NMR (300 MHz, MeOH-
d4) δ ppm 8.87 (s, 1H), 8.52 (t, J ) 1.7 Hz, 1H), 8.29 (d, J ) 1.7
Hz, 1H), 8.27 (d, J ) 2.0 Hz, 1H), 7.93 (t, J ) 7.6 Hz, 1H), 7.66
(d, J ) 0.68 Hz, 1H), 7.44-7.56 (m, 1H), 7.23-7.34 (m, 1H),
5.41 (br s, 1H), 4.79 (br s, 1H), 3.70-3.82 (m, 1H), 3.35-3.53
(m, 3H), 3.25 (s, 3H), 2.02-2.20 (m, 2H). MS (ESI) m/z 463 (M
+ H)+. Anal. (C22H21F3N4O2S‚2HCl‚H2O) C, H, N, Cl.
iv
po
31
34
42
2.18
1.81
0.19
1.04
1.24
1.28
192
710
1997
0.42
1.8
7.8
223
771
24 350
9.0
27.6
90.3
a All PK was measured in rats (n ) 6) at 5 mg/kg dose. CLp, plasma
clearance; Vss, volume of distribution at steady state; Cmax, maximal
concentration when dosed orally; t1/2, terminal half-life when dosed orally;
AUC, area under curve; F, oral bioavailability. For structures, see Tables
1 and 2.
of the enzyme, and the amine group forms an electrostatic
interaction with the side chains of Glu205 and Glu206 in both
complexes. In the case of the 31/DPP4 complex, while the
lactam carbonyl of 31 does not form any specific interaction
with the enzyme, the methylenedioxyphenyl group forms a
hydrophobic interaction with the side chain of Phe357. This
binding mode explains why analog 21 with a three-carbon linker
is much less potent: the chain is too long to maintain the same
hydrophobic interaction without suffering an entropic penalty.
One of the oxygen atoms of the methylenedioxyphenyl group
may form a hydrogen bond with the NH of Arg358 side chain
(3.2 Å). In the case of the 42/DPP4 complex, the trajectory of
the nitrogen is different from that of the 31/DPP4 complex such
that a π-π interaction is formed between the pyrimidine ring
of the ligand and the phenyl ring of Phe357.
Acknowledgment. The authors thank Jianguo Ji and David
Barnes for helpful discussion, Abbott structural chemistry
department for NMR assistance, Zhenping Tian for providing
26, Paul West for HRMS, high-throughput purification (HTP)
group for purification, and Michael Serby for proofreading.
Pharmacokinetic (PK) parameters of selected inhibitors are
shown in Table 4. While methylenedioxy piperidinone 31 has
a very high clearance (2.18 L/hr‚Kg) and low oral bioavailability
(9.0%), sulfone 34, where the methylenedioxy was replaced with
methylsulfonyl, has a reduced clearance (1.81 L/hr‚Kg) and
improved oral bioavailability (27.6%). Further PK improvement
was achieved in 42, where the flexible linker was replaced with
a more rigid and more polar pyrimidine ring. Thus, sulfone 42
has a very low clearance (0.19 L/hr‚Kg), a long half-life (7.8
h), and high oral bioavailability (90%). All three compounds
show very similar volumes of distribution (1.04 to 1.28 L/Kg).
Supporting Information Available: Experimental procedures,
including characterization data for intermediates and final products,
X-ray data, and refinement of crystal structures of human DPP4
complexed with inhibitors. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) See: www.diabetes.org.
In summary, starting from a HTS hit, we were able to identify
a series of piperidinone- and piperidine-constrained phenethy-
lamines as novel DPP4 inhibitors. A new asymmetric synthetic
methodology was applied to synthesize these analogs in optically
pure form. X-ray crystallographic data show that halogenated
phenyl rings occupy the S1 pocket. The middle piperidinone
and piperidine rings act to orient the exocyclic primary amino
group and the appendages off the endocyclic nitrogen atom in
the correct directions. Optimized compounds are potent, selec-
tive, and exhibit good to excellent PK.
(2) Kim, D.; Wang, L.; Beconi, M.; Eiermann, G. J.; Fisher, M. H.; He,
H.; Hickey, G. J.; Kowalchick, J. E.; Leiting, B.; Lyons, K.; Marsilio,
F.; McCann, M. E.; Patel, R. A.; Petrov, A.; Scapin, G.; Patel, S. B.;
Roy, R. S.; Wu, J. K.; Wyvratt, M. J.; Zhang, B. B.; Zhu, L.;
Thornberry, N. A.; Weber, A. E. (2R)-4-Oxo-4-[3-(trifluoromethyl)-
5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluo-
rophenyl)-butan-2-amine: A potent, orally active dipeptidyl peptidase
IV inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2005,
48, 141-151.
(3) Miller, S. A.; St. Onge, E. L. Sitagliptin: A dipeptidyl peptidase IV
inhibitor for the treatment of Type 2 diabetes. Ann. Pharmcother.
2006, 40, 1336.

Brief Articles
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8 1987
(4) Villhauer, E. B.; Brinkman, J. A.; Naderi, G. B.; Burkey, B. F.;
Dunning, B. E.; Prasad, K.; Mangold, B. L.; Russell, M. E.; Hughes,
T. E. 1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrro-
lidine: A potent, selective, and orally bioavailable dipeptidyl
peptidase IV inhibitor with antihyperglycemic properties. J. Med.
Chem. 2003, 46, 2774-2789.
(5) Augeri, D. J.; Robl, J. A.; Betebenner, D. A.; Magnin, D. R.; Khanna,
A.; Robertson, J. G.; Wang, A.; Simpkins, L. M.; Taunk, P.; Huang,
Q.; Han, S-P.; Abboa-Offei, B.; Cap, M.; Xin, L.; Tao, L.; Tozzo,
E.; Welzel, G. E.; Egan, D. M.; Marcinkeviciene, J.; Chang, S. Y.;
Biller, S. A.; Kirby, M. S.; Parker, R. A.; Hamann, L. G. Discovery
and preclinical profile of saxagliptin (BMS-477118): A highly potent,
long-acting, orally active dipeptidyl peptidase IV inhibitor for the
treatment of type 2 diabetes. J. Med. Chem. 2005, 48, 5025-5037.
(6) Gwaltney, S. L.; Aertgeerts, K.; Feng, J.; Kaldor, S. W.; Kassel, D.
B.; Manuel, M.; Navre, M.; Prasad, G. S.; Shi, L.; Skene, R. J.;
Stafford, J. A.; Wallace, M.; Xu, R.; Ye, S.; Zhang, Z. Abstracts of
Papers, 231st Meeting of the American Chemical Society, Atlanta,
GA, 2006; American Chemical Society: Washington, DC, 2006;
MEDI-018.
(7) Madar, D. J.; Kopecka, H.; Pireh, D.; Yong, H.; Pei, Z.; Li, X.;
Wiedeman, P.; Djuric, S. W.; von Geldern, T. W.; Fickes, M.;
Bhagavatula, L.; McDermott, T.; Wittenberger, S.; Richards, S. J.;
Longenecker, K.; Stewart, K.; Lubben, T. H.; Ballaron, S. J.; Stashko,
M. A.; Long, M.; Wells, H.; Zinker, B. A.; Mika, A. K.; Beno, D.
W. A. Kempf-Grote, A. J.; Polakowski, J.; Segreti, J.; Reinhart, G.
A.; Fryer, R.; Sham, H. L.; Trevilliyan, J. M. Discovery of 2-[4-
{{2-(2S,5R)-2-cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]-4-
methyl-1-piperidinyl]-4-pyridinecarboxylic acid (ABT-279); a very
potent, selective, effective, and well-tolerated inhibitor of dipeptidyl
peptidase-IV, useful for the treatment of diabetes. J. Med. Chem.
2006, 49, 6416-6420.
(8) For reviews on DPP4 inhibitors, see (a) Green, B. D.; Flatt, P. R.;
Bailey, C. J. Inhibition of dipeptidyl peptidase IV activity as a therapy
of type 2 diabetes. Expert Opin. Emerging Drugs 2006, 11, 525-
539. (b) Gwaltney, S. L., II; Stafford, J. A. Inhibitors of dipeptidyl
peptidase 4. Annu. Rep. Med. Chem. 2005, 40, 149-165. (c) Weber,
A. E. Dipeptidyl peptidase IV inhibitors for the treatment of diabetes.
J. Med. Chem. 2004, 47, 4135-4141. (d) Villhauer, E. B.; Coppola,
G. M; Hughes, T. E. DPPIV inhibition and therapeutic potential.
Annu. Rep. Med. Chem. 2001, 36, 191-200.
(15) Pei, Z.; Li, X.; von Geldern, T. W.; Madar, D. J.; Longenecker, K.;
Yong, H.; Lubben, T. H.; Stewart, K. D.; Zinker, B. A.; Backes, B.
J.; Judd, A. S.; Mulhern, M.; Ballaron, S. J.; Stashko, M. A.; Mika,
A. K.; Beno, D. W. A.; Reinhart, G. A.; Fryer, R. M.; Preusser, L.
C.; Kempf-Grote, A. J.; Sham, H. L.; Trevillyan, J. M. Discovery of
((4R,5S)-5-Amino-4-(2,4,5- trifluorophenyl)-cyclohex-1-enyl)-(3-(tri-
fluoromethyl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-
methanone (ABT-341), a highly potent, selective, orally efficacious,
and safe dipeptidyl peptidase IV inhibitor for the treatment of type
2 diabetes. J. Med. Chem. 2006, 49, 6439-6442.
(16) Backes, B. J.; Longenecker, K.; Hamilton, G. L.; Stewart, K.; Lai,
C.; Kopecka, H.; von Geldern, T. W.; Madar, D. J.; Pei, Z.; Lubben,
T. H.; Zinker, B. A.; Tian, Z.; Ballaron, S. J.; Stashko, M. A.; Mika,
A. K.; Beno, D. W. A.; Kempf-Grote, A. J.; Black-Schaefer, C.;
Sham, H. L.; Trevillyan, J. M. Pyrrolidine-constrained phenethy-
lamines: The design of potent, selective and pharmacologically
efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-
like screening hit. Bioorg. Med. Chem. Lett. 2007, doi: 10.1016/
j.bmcl.2007.01.026.
(17) Ono, N.; Kamimura, A.; Kaji, A. Michael addition of secondary
nitroalkanes to â-substituted R,â-unsaturated compounds. Synthesis
1984, 226-227.
(18) Klapars, A.; Huang, X.; Buchwald, S. L. A general and efficient
copper catalyst for the amidation of aryl halides. J. Am. Chem. Soc.
2002, 124, 7421-7428.
(19) The details of this new methodology will be published elsewhere.
(20) (a) Ji, J.; Barnes, D. M.; Zhang, J.; King, S. A.; Wittenberger, S. J.;
Morton, H. E. Catalytic enantioselective conjugate addition of 1,3-
dicarbonyl compounds to nitroalkenes. J. Am. Chem. Soc. 1999, 121,
10215-10216. (b) Barnes, D. M.; Ji, J.; Fickes, M. G.; Fitzgerald,
M. A.; King, S. A.; Morton, H. E.; Plagge, F. A.; Preskill, M.;
Wagaw, S. H.; Wittenberger, S. J.; Zhang, J. Development of a
catalytic enantioselective conjugate addition of 1,3-dicarbonyl com-
pounds to nitroalkenes for the synthesis of endothelin-A antagonist
ABT-546. Scope, mechanism, and further application to the synthesis
of the antidepressant Rolipram. J. Am. Chem. Soc. 2002, 124, 13097-
13105.
(21) For details, see Supporting Information.
(22) (a) Corey, E. J.; Guzman-Perez, A.; Loh, T. P. Demonstration of the
synthetic power of oxazaborolidine-catalyzed enantioselective Diels-
Alder reactions by very efficient routes to cassiol and gibberellic
acid. J. Am. Chem. Soc. 1994, 116, 3611-3612. (b) For a review,
see: Krapcho, A. P. Synthetic applications of dealkoxycarbonylations
of malonate esters, â-keto esters, R-cyano esters and related
compounds in dipolar aprotic mediasPart I. Synthesis 1982, 805-
914.
(23) For details of the assay, see: Pei, Z.; Li, X.; Longenecker, K.; von
Geldern, T. W.; Wiedeman, P. E.; Lubben, T. H.; Zinker, B. A.;
Stewart, K.; Ballaron, S. J.; Stashko, M. A.; Mika, A. K.; Beno, D.
W. A.; Long, M.; Wells, H.; Kempf-Grote, A. J.; Madar, D. J.;
McDermott, T. S.; Bhagavatula, L.; Fickes, M. G.; Pireh, D.;
Solomon, L. R.; Lake, M. R.; Edalji, R.; Fry, E. H.; Sham, H. L.;
Trevillyan, J. M. Discovery, structure-activity relationship, and
pharmacological evaluation of (5-substituted-pyrrolidinyl-2-carbonyl)-
2-cyanopyrrolidines as potent dipeptidyl peptidase IV inhibitors. J.
Med. Chem. 2006, 49, 3520-3535.
(24) (a) Cox, J. M.; Edmondson, S. D.; Harper, B.; Weber, A. E.
Aminopiperidines as dipeptidyl peptidase-IV inhibitors for the
treatment or prevention of diabetes. PCT Int. Appl. WO 2006039325,
2006. (b) Edmondson, S. D.; Mastracchio, A.; Cox, J. M. Fused
aminopiperidinobenzimidazoles as dipeptidyl peptidase-IV inhibitors,
their preparation, pharmaceutical compositions, and use for the
treatment or prevention of diabetes. PCT Int. Appl. WO 2006058064,
2006.
(25) Lankas, G. R.; Leiting, B.; Roy, R. S.; Eiermann, G. J.; Beconi, M.
G.; Biftu, T.; Chan, C-C.; Edmondson, S.; Feeney, W. P.; He, H.;
Ippolito, D. E.; Kim, D.; Lyons, K. A.; Ok, H. O.; Patel, R. A.; Petrov,
A. N.; Pryor, K. A.; Qian, X.; Reigle, L.; Woods, A.; Wu, J. K.;
Zaller, D.; Zhang, Z.; Zhu, L.; Weber, A. E.; Thornberry, N. A.
Dipeptidyl peptidase IV inhibition for the treatment of type 2
diabetes: Potential importance of selectivity over dipeptidyl pepti-
dases 8 and 9. Diabetes 2005, 54, 2988-2994.
(9) (a) Mojsov, S.; Weir. G. C; Habener, J. F. Insulinotropin: Glucagon-
like peptide I (7-37) co-encoded in the glucagon gene is a potent
stimulator of insulin release in the perfused rat pancreas. J. Clin.
InVest. 1987, 79, 616-619. (b) Kreymann, B.; Ghatei, M. A.;
Williams, G.; Bloom, S. R. Glucagon-like peptide-1 7-36:
A
physiological incretin in man. Lancet 1987, 2, 1300-1304. (c)
Orskov, C.; Holst, J. J.; Nielsen, O. V. Effect of truncated glucagon-
like peptide-1 [proglucagon-(78-107) amide] on endocrine secretion
from pig pancreas, antrum, and nonantral stomach. Endocrinology
1988, 123, 2009-2013.
(10) Nauck, M. A.; Heimesaat, M. M.; Behle, K.; Holst, J. J.; Nauck, M.
S.; Ritzel, R.; Hufner, M.; Schmiegel. W. H. Effects of glucagon-
like peptide 1 on counterregulatory hormone responses, cognitive
functions, and insulin secretion during hyperinsulinemic, stepped
hypoglycemic clamp experiments in healthy volunteers. J. Clin.
Endocrinol. Metab. 2002, 87, 1239-1246.
(11) (a) Wettergren, A.; Schjoldager, B.; Mortensen, P. E.; Myhre, J.;
Christiansen, J.; Holst, J. J. Truncated GLP-1 (proglucagon 78-107-
amide) inhibits gastric and pancreatic functions in man. Dig. Dis.
Sci. 1993, 38, 665-673. (b) Nauck, M. A.; Niedereichholz, U.; Ettler,
R.; Holst, J. J.; Orskov, C.; Ritzel, R.; Schmiegel, W. H. Glucagon-
like peptide 1 inhibition of gastric emptying outweighs its insulino-
tropic effects in healthy humans. Am. J. Physiol. 1997, 273, E981-
E988.
(12) Holst, J. J. On the physiology of GIP and GLP-1. Horm. Metab.
Res. 2004, 36, 747-754.
(13) Meier, J. J. Glucose-dependent insulinotropic polypeptide/gastric
inhibitory polypeptide. Best Pract. Res., Clin. Endocrinol. Metab.
2004, 18, 587-606.
(14) (a) Mentlein, R.; Ballwitz, B.; Schmidt, W. E. Dipeptidylpeptidase
IV hydrolyses gastric inhibitory polypeptide, glucagonlike peptide-
1(7-36)amide, peptide histidine methionine and is responsible for
their degradation in human serum. Eur. J. Biochem. 1993, 214, 829-
835. (b) Kieffer, T. J.; McIntosh, C. H. S.; Pederson, T. A.
Degradation of glucose-dependent insulinotropic polypeptide and
truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl
peptidase IV. Endocrinology 1995, 136, 3585-3596. (c) For a review,
see: Deacon, C. F. Circulation and degradation of GIP and GLP-1.
Horm. Metab. Res. 2004, 36, 761-765.
(26) Refined crystallographic coordinates for the structures of DPP4
complexed with 31 and 42 have been deposited in Protein Data Bank
(www.rcsb.org) with entry codes 2OQI and 2OQV, respectively.
JM061436D