4-Aminophenylalanine and 4-aminocyclohexylalanine derivatives as potent, selective, and orally bioavailable inhibitors of dipeptidyl peptidase IV

Article abstract of DOI:10.1016/j.bmcl.2007.02.066

A novel series of 4-aminophenylalanine and 4-aminocyclohexylalanine derivatives were designed and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4). The phenylalanine series afforded compounds such as 10 that were potent and selective (DPP-4, IC<

Full text of DOI:10.1016/j.bmcl.2007.02.066

Bioorganic & Medicinal Chemistry Letters 17 (2007) 2879–2885
4-Aminophenylalanine and 4-aminocyclohexylalanine derivatives as
potent, selective, and orally bioavailable inhibitors of
dipeptidyl peptidase IV
Joseph L. Duffy,a,* Brian A. Kirk,a Liping Wang,a George J. Eiermann,b Huaibing He,a
Barbara Leiting,c Kathryn A. Lyons,a Reshma A. Patel,c Sangita B. Patel,a
Alexsandr Petrov,b Giovanna Scapin,a Joseph K. Wu,c
Nancy A. Thornberryc and Ann E. Webera
aDepartment of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA
bDepartment of Pharmacology, Merck Research Laboratories, Rahway, NJ 07065, USA
cDepartment of Metabolic Disorders, Merck Research Laboratories, Rahway, NJ 07065, USA
Received 18 December 2006; revised 19 February 2007; accepted 21 February 2007
Available online 25 February 2007
Abstract—A novel series of 4-aminophenylalanine and 4-aminocyclohexylalanine derivatives were designed and evaluated as inhib-
itors of dipeptidyl peptidase IV (DPP-4). The phenylalanine series afforded compounds such as 10 that were potent and selective
(DPP-4, IC50 = 28 nM), but exhibited limited oral bioavailability. The corresponding cyclohexylalanine derivatives such as 25 affor-
ded improved PK exposure and efficacy in a murine OGTT experiment. The X-ray crystal structure of 25 bound to the DPP-4 active
site is presented.
Ó 2007 Elsevier Ltd. All rights reserved.
Type 2 diabetes mellitus may be effectively treated by
agents that induce the biosynthesis and secretion of insu-
lin during periods of hyperglycemia. Two endogenous
peptides that stimulate glucose-dependent insulin secre-
tion are the incretin hormones glucagon-like peptide 1
(GLP-1) and glucose-dependent insulinotropic polypep-
tide (GIP).1 Infusion of GLP-1 in patients with type 2
diabetes has resulted in significant decreases in plasma
glucose and hemoglobin A1c levels.2 Due to the rapid
inactivation of GLP-1 by the serine protease dipeptidyl
peptidase IV (DPP-4) this hormone must be adminis-
tered by chronic intravenous administration to achieve
sustained efficacy.2 An alternative approach to increase
the level of circulating GLP-1 involves the inhibition of
DPP-4, and this method has emerged as an important
potential therapy for the treatment of type 2 diabetes.3
the development of a structurally diverse collection of
potent DPP-4 inhibitors that lack significant inhibitory
activity of the related proline-specific peptidases QPP,
DPP8, and DPP9.5 Inhibitory selectivity for DPP-4 over
DPP8 and DPP9 was particularly emphasized. The inhi-
bition of the latter two enzymes has been associated with
profound toxicity in preclinical studies, although the rel-
evance of this toxicity to humans has not been
established.6
The threo isoleucyl thiazolidine 1 affords superior DPP-4
selectivity over the allo isomer 2 (Fig. 1),6 and this dis-
covery led to the development of selective b-substituted
phenylalanine derived inhibitors 3 and 4.7 The latter two
compounds represented significant advancements in
DPP-4 potency, peptidase selectivity, and oral bioavail-
ability, but each retained significant off-target activity
against the human cardiac ion channel hERG
(IC50 = 1–5 lM). In a recent report from these laborato-
ries, the selectivity of this class was improved with the
incorporation of fused heterocycles such as 5 in the dis-
tal aromatic ring (hERG, IC50 = 86 lM).7c Here we de-
scribe a complementary effort to decrease the lipophilic
character of this lead class, and improve selectivity over
Multiple small molecule DPP-4 inhibitors have been re-
ported.4 Research in these laboratories has focused on
Keywords: Dipeptidyl peptidase IV; DPP-4; Kazmaier Claisen; Buch-
wald amidation; X-ray.
*
Corresponding author. E-mail: joseph_duffy@merck.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.02.066

2880
J. L. Duffy et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2879–2885
O
O
N
N
+
NH3
+
S
NH3
S
2
1
DPP-4 = 460 nM
QPP = 18000 nM
DPP8 = 220 nM
DPP9 = 320 nM
DPP-4 = 420 nM
QPP = 14000 nM
DPP8 = 2180 nM
DPP9 = 1600 nM
IC50
IC50
R
O
N
O
O
N
N
+
NH3
+
NH3
N
N
N
F
3 R = CON(Me)2
4 R = Me
F
F
5
H
Ar
N
S
O
O
O
N
+
NH3
F
6 Ar = 2,4-diFPh
Figure 1. DPP-4 inhibitors.
hERG, by incorporating the structural features of the
related cyclohexylglycine lead class of DPP-4 inhibitors
such as 6 (hERG, IC50 = 49 lM, Table 4).8
resulted in substantial gains in potency, and these com-
pounds retained outstanding peptidase selectivity. The
corresponding acetamide 12 and N-methyl acetamide
14 were less potent inhibitors of DPP-4. The b-dimeth-
ylamide substituent was previously found to enhance
potency and selectivity over the b-methyl substituent,
as with 3 and 4,7b and this trend was retained in the ami-
no phenylalanine derivative series. The b-dimethylamide
derivatives 10, 12, and 14 were uniformly more potent
than the corresponding b-methyl analogues.
Our initial endeavor focused on the incorporation of
4-aminophenylalanine substituents as a replacement
for the biphenyl moiety in 3 and 4, and the synthesis
of the sulfonamide 7 from this design is illustrated in
Scheme 1. The b-dimethylamide aryl bromide I was pre-
pared using Kazmaier’s enolate–Claisen rearrangement
as described previously.7c This intermediate was con-
verted directly to the desired N-aryl amide or N-aryl sul-
fonamide by application of the copper-mediated
amidation reaction developed by Buchwald and cowork-
ers.9 We found that the addition of a full equivalent of
CuI and three equivalents of the diamine ligand afforded
reproducibly high yielding coupling of the sulfonamide
and amide substituents, although no further optimiza-
tion of the reaction conditions was attempted.10 The
corresponding b-methyl derivatives were prepared in a
similar fashion from the corresponding aryl bromide
intermediate that has also been described previously.7a
The pharmacodynamic characterization of 3, reported
previously,7b revealed a lower than expected efficacy
in the murine OGTT experiment. This was attributed
to a shift toward lower DPP-4 inhibitory potency in
the presence of human or mouse serum. As illustrated
in Table 2, the incorporation of the amide substituent
in 10 afforded somewhat improved potency compared
to compound 3 in the presence of 50% human serum
(IC50 = 0.16 lM). Compound 10 also afforded a sub-
stantial improvement over 3 in selectivity in the cardiac
hERG binding assay. However, compound 10 exhib-
ited comparatively poor oral bioavailability when
dosed in rats, as illustrated by the lower dose-normal-
ized oral AUC (nAUC) and higher clearance rate (Clp)
(Table 2).
The compounds synthesized were assayed for their
inhibitory potency against the DPP-4 enzyme, as well
as their selectivity over the related proline-specific en-
zymes QPP (DPP-II), DPP8, and DPP9, and the results
are summarized in Table 1.11
We sought to improve the pharmacokinetic properties
of the lead class while preserving the selectivity and
the decreased influence of serum on intrinsic potency.
In previous reports from these laboratories, a series of
4-aminocyclohexylglycine amides and sulfonamides
such as 6 (Fig. 1) were presented.8 Many of these deriv-
atives afforded acceptable PK profiles, but suffered from
poor inhibitory selectivity over DPP8 and DPP9. We
reasoned that we could combine the high peptidase
Substitution of the biaryl species in 3 or 5 with the aryl-
sulfonamide 7 resulted in a substantial loss of potency
toward DPP-4 (Table 1). The N-methyl toluyl sulfon-
amide derivative 8 was somewhat more potent, but the
DPP-4
inhibitory
activity
remained
modest
(IC50 = 0.43 lM). Substitution of the aryl sulfonamide
moiety in 7 with the benzamide moiety in 9 and 10

J. L. Duffy et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2879–2885
2881
Br
TFA-
H
NHBoc
N
+
N
NH3
S
a, b
F
O
O
N
F
Me
O
O
N
Me
O
N
O
Me
Me
I
7
Scheme 1. Reagents and conditions: (a) PhSO2NH2 (2.5 equiv), K2CO3 (3 equiv), CuI (1 equiv), N,N0-dimethyl ethylene diamine (3 equiv), toluene,
110 °C (sealed tube), 48 h (80%); (b) TFA, CH2Cl2 (80%).
Table 1. Inhibitory properties of phenylalanine derivatives
R2
O
N
+
NH3
R1
TFA-
F
Compound
R1
R2
IC50 (lM)
DPP-4
QPP
DPP8
DPP9
3
4
CONMe2
Me
0.012
0.064
45
2.7
>100
87
69
86
F
N
N
N
5
7
8
9
CONMe2
CONMe2
CONMe2
CONMe2
0.004
0.87
>100
80
>100
>100
>100
>100
>100
>100
>100
>100
O
O
S
N
H
O
O
S
N
0.43
>100
>100
Me
Me
Me
O
0.025
N
Me
O
10
11
CONMe2
Me
0.028
0.30
>100
4.7
>100
>100
>100
>100
N
Me
F
O
O
12
13
CONMe2
Me
0.16
0.60
>100
70
60
82
>100
>100
Me
N
H
14
15
CONMe2
Me
0.15
0.21
>100
22
>100
>100
>100
>100
Me
N
Me
selectivity of the 4-aminophenylalanine class represented
by compound 10, and incorporate the desirable PK
profile of the 4-aminocyclohexylglycine class repre-
sented by 6. By merging the salient structural features
of these classes, we designed the 4-amino cyclohexylala-
nine compounds represented by 16 (Table 3).

2882
J. L. Duffy et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2879–2885
Table 2. Potency in the presence of 50% human serum, selectivity over hERG binding, and rat PK parameters
Compound
IC50 (lM)
DPP-4 (50% HS)
Rat PK(l/2mpk iv/po)
Clp (mL/min/kg)
hERG
nAUC (lM h/mpk)
F (%)
3
10
0.39
0.16
4.6
>90
6.23
0.03
4.8
73
67
6
Table 3. Inhibitory properties of cyclohexylalanine derivatives
R2
O
N
+
NH3
R1
Cl-
F
Compound
R1
R2
IC50 (lM)
DPP-4 (0% HS)
DPP-4 (50% HS)
DPP8
DPP9
F
O
O
6
16
17
0.048
0.33
0.46
0.99
>100
21
2.7
>100
42
S
CONMe2
Me
0.51
1.49
N
H
F
O
O
S
N
18
19
CONMe2
Me
0.36
0.44
1.28
3.47
>100
11
>100
26
H
F3C
F
O
O
20
21
CONMe2
Me
0.024
0.022
0.20
0.092
>100
6.3
>100
46
N
Me
O
22
23
Me
Me
0.074
0.027
0.21
29
30
63
46
N
Me
Me
H
O
O
0.097
N
Me
O
O
24
25
CONMe2
Me
0.029
0.016
0.19
0.040
>100
25
>100
>100
Me
N
Me
O
26
Me
0.021
0.047
12
29
N
Me
The synthesis of 16 is illustrated in Scheme 2. The ester
II was prepared from intermediate I via palladium cata-
lyzed carbonylation.12 Hydrogenation of the aromatic
group using platinum oxide afforded a 2:1 mixture of
cis and trans isomers. The mixture was hydrolyzed to
the acids, which were then treated with diphenylphos-
phoryl azide to effect the Curtius rearrangement. The
intermediate isocyanates were trapped with benzyl alco-
hol, affording the isomeric mixture of benzyl carbamate-
protected 4-aminocyclohexylalanine derivatives. The
isomeric mixture was separated at this point by prepara-
tive normal-phase HPLC, affording each of the single
diastereomers of IV. Removal of the benzyl carbamate
by hydrogenation was followed by derivatization of
the cyclohexylamine and removal of the Boc group,
affording the final product. In each instance, both dia-
stereomeric final products were prepared. The diastereo-
mers typically differed by fivefold in their inhibitory
potency of DPP-4, and only the data corresponding to
the more potent diastereomer are presented.13
The potency and selectivity of the cyclohexylalanine
derivatives are shown in Table 3, as well as the DPP-4
inhibitory potency of the compounds in the presence

J. L. Duffy et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2879–2885
2883
O
O
Br
CbzHN
F
d, e
NHBoc
N
NHBoc
N
NHBoc
N
NHBoc
N
BuO
HO
a
F
F
b, c
F
Me
O
O
Me
O
O
Me
O
O
Me
O
O
N
N
N
N
Me
Me
Me
Me
I
II
III
IV
TFA-
H
H2N
+
N
NHBoc
N
NH3
S
f
g, h
O
O
F
N
F
Me
O
O
Me
O
N
N
O
Me
Me
V
16
Scheme 2. Reagents and conditions: (a) BuOH, Et3N, Pd(DPPF)2 (10%), CO (1 atm), 90 °C, 18 h (71%); (b) H2 (3.8 atm), Pt2O (cat), AcOH, 48 h; (c)
LiOH, THF, MeOH; (d) DPPA, Et3N, toluene, 110 °C, 3.5 h, then BnOH, 110 °C (54%—4 steps, diastereomeric mixture); (e) HPLC (Chiracel OD,
10% EtOH / hexane); (f) H2 (3.5 atm), 10% Pd/C (cat), MeOH, 3 h (99%); (g) PhSO2Cl, DIEA, CH2Cl2; (h) HCl, dioxane (79%—2 steps).
of 50% human serum. Incorporation of the b-dimethyl-
amide or b-methyl substituent into 6 afforded the homo-
logues 16 and 17. The latter two compounds exhibited
diminished inhibitory potency of DPP-4, but retained
a more favorable selectivity profile over DPP8 and
DPP9. Additional sulfonamide derivatives such as 18
and 19 were prepared, and these were similarly less po-
tent than the analogous compounds in the 4-amin-
ocyclohexylalanine series.8 A substantial improvement
in potency was realized with amide derivatives such as
20 and 21. While the b-dimethylamide derivative 20
retained greater selectivity over DPP8 and DPP9, the
b-methyl derivative 21 retained greater intrinsic potency
in the presence of human serum. This correlation was
observed in 24 and 25, as well as multiple other members
of this lead class (data not shown). The N-methyl ter-
tiary cyclohexylamide derivatives such as 23 afforded
somewhat improved potency over the secondary amide
derivatives such as 22. Replacement of the aromatic
benzamide substituent with the smaller aliphatic amides
as in 24–27 afforded a further slight improvement in
intrinsic potency, both in the absence and presence of
human serum.
acetamide derivatives 24 and 25, with the
b-methyl substituted 25 affording substantially improved
oral bioavailability. The cyclopropyl acetamide deriva-
tive 26 afforded a similar PK profile to the acetamide 25,
albeit with diminished selectivity over the hERG channel
and DPP8 (Table 3). The acetamide derivative 25 was fur-
ther profiled in a canine PK experiment, and the com-
pound maintained good oral bioavailability.
The X-ray crystal structure determination of the
acetamide 25 co-crystallized with DPP-4 is shown in
Figure 2.14 Compound 25 (yellow) maintains similar en-
zyme interactions to those previously reported with
inhibitor 5 (magenta) in the S1 hydrophobic pocket
and amino group binding residues.7c The b-methyl sub-
stituent in 25 does not maintain the productive hydro-
gen bonding interaction with Tyr547 that is evident in
the b-dimethylamide derivative 5. However, the poten-
tial benefit of this interaction may be mitigated in these
cyclohexylalanine derivatives, as suggested by the simi-
lar intrinsic potency of the b-methyl derivative 25 with
the b-dimethylamide analogue 24 (Table 3). The cyclo-
hexyl moiety in 25 precludes the edge to face p–p inter-
action with Phe357 that has been implicated in related
structures.15 The cyclohexyl ring does provide an ade-
quate tether for the terminal acetamide substituent to
maintain a hydrophobic interaction with Phe357, and
a hydrogen bonding interaction with Arg358.
Several of the derivatives in Table 3 were profiled further
for off-target activity, as indicated by binding to the
hERG ion channel, and in PK experiments. The results
are shown in Table 4. The b-methyl derivative 21 afforded
greater oral exposure (nAUC) than the related b-dimeth-
ylamide derivative 20, but 21 also exhibited higher clear-
ance. This correlation was more pronounced in the
The efficacy of the acetamide derivative 25 was investi-
gated in an oral glucose tolerance test (OGTT) in lean
Table 4. hERG binding and PK parameters in rat and dog for selected DPP-4 inhibitors
Compound
hERG (lM)
PK (1/2 mpk iv/po)
Species
nAUC (lM h/mpk)
CLp (mL/min/kg)
F (%)
6
20
21
24
25
49
Rat
Rat
Rat
Rat
Rat
Dog
Rat
0.90
0.31
0.74
0.09
0.68
9.82
0.44
24
27
40
18
42
4.4
49
53
25
72
3
>90
78
>90
>90
56
83
46
26
39

2884
J. L. Duffy et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2879–2885
2. Holst, J. J. Diabetologia 2006, 49, 253; Drucker, D. J. Cell
Metab. 2006, 3, 153; Zander, M.; Madsbad, S.; Madsen, J.
L.; Holst, J. J. Lancet 2002, 359, 824.
3. Deacon, C. F.; Holst, J. J. Int. J. Biochem. Cell Biol. 2006,
38, 831; Demuth, H.-U.; McIntosh, C. H. S.; Pederson, R.
A. Biochim. Biophys. Acta 2005, 1751, 33.
4. Augustyns, K.; Van der Veken, P.; Haemers, A. Expert
Opin. Ther. Pat. 2005, 15, 1354; Weber, A. E. J. Med.
Chem. 2004, 47, 4135.
5. Rosenblum, J. S.; Kozarich, J. W. Curr. Opinion Chem.
Biol. 2003, 7, 496; Sedo, A.; Malik, R. Biochem. Biophys.
Acta 2001, 1550, 107.
6. Lankas, G. R.; Leiting, B.; Sinha Roy, R.; Eiermann, G.
J.; Biftu, T.; Cahn, C.-C.; Edmondson, S. D.; 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, X.;
Zhu, L.; Weber, A. E.; Thornberry, N. A. Diabetes 2005,
54, 2988.
7. (a) Xu, J.; Wei, L.; Mathvink, R.; He, J.; Park, Y.-J.; He,
H.; Leiting, B.; Lyons, K. A.; Marsilio, F.; Patel, R. A.;
Wu, J. K.; Thornberry, N. A.; Weber, A. E. Bioorg. Med.
Chem. Lett. 2005, 15, 2533; (b) Edmondson, S. D.;
Mastracchio, A.; Duffy, J. L.; Eiermann, G. J.; He, H.;
Ita, I.; Leiting, B.; Leone, J. F.; Lyons, K. A.; Mak-
arewicz, A. M.; Patel, R. A.; Petrov, A.; Wu, J. K.;
Thornberry, N. A.; Weber, A. E. Bioorg. Med. Chem. Lett.
2005, 15, 3048; (c) Edmondson, S. D.; Mastracchio, A.;
Mathvink, R. J.; He, J.; Harper, B.; Park, Y.-J.; Beconi,
M.; Di Salvo, J.; Eiermann, G. J.; He, H.; Leiting, B.;
Leone, J. F.; Levorse, D. A.; Lyons, K.; Patel, R. A.;
Patel, S. B.; Petrov, A.; Scapin, G.; Shang, J.; Sinha Roy,
R.; Smith, A.; Wu, J. K.; Xu, S.; Zhu, B.; Thornberry, N.
A.; Weber, A. E. J. Med. Chem. 2006, 49, 3614.
8. Parmee, E. R.; He, J.; Mastracchio, A.; Edmondson, S.
D.; Colwell, L.; Eiermann, G.; Feeney, W. P.; Habulihaz,
B.; He, H.; Kilburn, R.; Leiting, B.; Lyons, K.; Marsilio,
F.; Patel, R. A.; Petrov, A.; Di Salvo, J.; Wu, J. K.;
Thornberry, N. A.; Weber, A. E. Bioorg. Med. Chem. Lett.
2004, 14, 43; Caldwell, C. G.; Chen, P.; He, J.; Parmee, E.
R.; Leiting, B.; Marsilio, F.; Patel, R. A.; Wu, J. K.;
Eiermann, G. J.; Petrov, A.; He, H.; Lyons, K. A.;
Thornberry, N. A.; Weber, A. E. Bioorg. Med. Chem. Lett.
2004, 14, 1265.
Figure 2. Compound 25 bound to the active site of DPP-4. The
overlay of 25 (yellow) with 5 (magenta, 2FJP.pdb) shows the similar
orientation of the two molecules. The interactions of 25 with DPP-4
are shown as red dotted lines.
mice. The compound reduced blood glucose excursion
in a dose-dependent manner from 0.1 mpk (ꢀ26%) to
3.0 mpk (ꢀ56%). This level of efficacy was not improved
over that observed previously with 3 in an identical
experiment, despite the diminished influence of serum
on the intrinsic potency of 25 (Tables 2 and 3).7b How-
ever, compound 25 afforded a substantially lower oral
exposure (nAUC) than 3 in rat PK studies (Tables 2
and 4). The diminished oral exposure, if operative in
mice as well, may have mitigated the improvements in
serum-shifted intrinsic potency achieved with 25.
The incorporation of structural features of the 4-amin-
ocyclohexylalanine lead series into the b-substituted
phenylalanine lead class of dipeptidyl peptidase IV
inhibitors afforded compounds with similar intrinsic
potency and diminished off-target activity. Further-
more, the derivatives incorporating the b-methyl substi-
tuent retained substantial potency in the presence of
human serum. However, the lower oral exposure at-
tained with these compounds may be the cause of the
lack of improved efficacy observed with 25 as com-
pared to analogous prior leads. Further optimization
of the PK exposure of this class is underway, and will
be reported in due course.
9. Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 7421.
10. For a related microwave-assisted sulfonamide arylation
using catalytic CuI, see He, H.; Wu, Y.-J. Tetrahedron
Lett. 2003, 44, 3385.
11. For assay conditions for the DPP-4 and QPP inhibition,
see Leiting, B.; Pryor, K. D.; Wu, J. K.; Marsilio, F.;
Patel, R. A.; Craik, C. S.; Ellman, J. A.; Cummings, R. T.;
Thornberry, N. A. Biochem. J. 2003, 371, 525; For assay
conditions for DPP8 and DPP9, see Ref. 6.
12. Vinogradov, S. A.; Wilson, D. F. Tetrahedron Lett. 1998,
39, 8935.
Acknowledgments
13. The X-ray crystal structure of 25 bound to the active site
of DPP-4 (Fig. 2) established unambiguously the 1,4-trans
relationship of the cyclohexyl substituents in this deriva-
tive. The single diastereomers 16–26 are all presumed to be
trans by analogy.
14. The structure of DPP-4 in a complex with 25 has been
deposited (PDB code 2OPH, RCSB ID code rcsb041425);
An alternative binding mode for compounds with similar
structural homology was recently discovered in these
laboratories. See Xu, J.; Wei, L.; Mathvink, R. J.;
Edmondson, S. D.; Eiermann, G. J.; He, H.; Leone, J.
F.; Leiting, B.; Lyons, K. A.; Marsilio, F.; Patel, R. A.;
Patel, S. B.; Petrov, A.; Scapin, G.; Wu, J. K.; Thornberry,
We are very grateful to Donald Hora, Judy Fenyk-Mel-
ody, Irene Capodanno, Paul Cunningham, Marcie Don-
nelly, James Hausamann, Christian Nunes, Xiaolan
Shen, John Strauss, and Kenneth Vakerich for in vivo
pharmacokinetic studies.
References and notes
1. Gautier, J. F.; Fetita, S.; Sobngwi, E.; Salaun-Marin, C.
Diabetes Metab. 2005, 31, 233.

J. L. Duffy et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2879–2885
2885
N. A.; Weber, A. E. Bioorg. Med. Chem. Lett. 2006, 16,
5373.
15. Qiao, L.; Baumann, C. A.; Crysler, C. S.; Ninan, N. S.;
Abad, M. C.; Spurlino, J. C.; DesJarlais, R. L.; Kervinen,
J.; Neeper, M. P.; Bayoumy, S. S.; Williams, R.; Deck-
man, I. C.; Dasgupta, M.; Reed, R. L.; Huebert, N. D.;
Tomczuk, B. E.; Moriarty, K. J. Bioorg. Med. Chem. Lett.
2006, 16, 123.