Aminomethylpyridines as DPP-IV inhibitors

Article abstract of DOI:10.1016/j.bmcl.2004.04.049

In a novel series of DPP-IV inhibitors, a large increase of inhibitory activity was achieved by optimisation of aromatic substituents and conformational restriction.

Full text of DOI:10.1016/j.bmcl.2004.04.049

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3579–3580
Aminomethylpyridines as DPP-IV inhibitors
*
ꢀ
Jens-Uwe Peters, Silja Weber, Stephane Kritter, Peter Weiss, Angelina Wallier,
Daniel Zimmerli, Markus Boehringer, Matthias Steger and Bernd-Michael Loeffler
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland
Received 27 January 2004; revised 29 March 2004; accepted 8 April 2004
Abstract—In a novel series of DPP-IV inhibitors, a large increase of inhibitory activity was achieved by optimisation of aromatic
substituents and conformational restriction.
Ó 2004 Elsevier Ltd. All rights reserved.
Glucagon-like peptide 1 (GLP-1) has recently attracted
attention as a new target for the treatment of type 2
diabetes.1 GLP-1 is secreted by the gastrointestinal tract
in response to food intake to stimulate insulin secre-
tion.2 Elevated levels of GLP-1 lead to an increased
insulin release and an improved glycaemic control in
type 2 diabetic patients.3 The level of circulating GLP-1
can be increased by inhibition of dipeptidyl peptidase IV
(DPP-IV),4 which is responsible for the rapid degrada-
tion of this hormone.5 Consequently, DPP-IV inhibitors
have been explored as potential new medicines.6
the piperonyl substituent of 1 by a 2,4-dichlorophenyl
substituent has led to a large activity increase in the
pyrimidine series.8 The structural similarity between the
pyrimidine and the pyridine series prompted us to
prepare the corresponding dichlorophenyl-pyridine 2b
(Table 1). As anticipated, 2b was about 50-fold more
active than 2a.
Rotational restriction was explored as a possibility of
further optimisation. The 6-phenyl–pyridine bond of 2b
can be locked by the introduction of an alkylidene tether
R (Table 1, 2c–e). The torsional minimum of the
phenyl–pyridine bond, as calculated by the program
Moloc (MAB force field),9 depends on the length of the
tether R, with shorter tethers leading to smaller angles.
Locking the torsion to smaller angles led to increasingly
active compounds, from 2c over 2d to 2e, with indeno-
pyridine 2e being three orders of magnitude more active
than 2a.
In a search for novel DPP-IV inhibitors, we identified
aminomethylpyrimidine 1 in a high-throughput screen.
As part of an evaluation of this screening hit, we pre-
pared 2a as a pyridine analogue of 1. Similar to 1, 2a
was found to be a weak inhibitor of DPP-IV.7
NH2 NH2
NH2
NH2
N
N
Table 1. Effect of conformational restriction on the inhibitory activi-
ties of 2
O
O
O
O
N
NH2
NH2
Cl
1
2a
N
HTS hit, IC50 = 10µM
IC50 = 47µM
6
R
Cl
To improve the weak inhibitory activity of 2a, we pre-
pared a number of derivatives 2b–k. The replacement of
R
Torsiona
IC50 (lM)
2b
2c
2d
2e
H, H
0.92
0.24
(CH2)3
(CH2)2
CH2
32°
22°
0°
* Corresponding author. Tel.: +41-61-6882636; fax: +41-61-6886459;
e-mail: jens-uwe.peters@roche.com
0.045
0.039
Present address: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16,
CH-4123 Allschwil, Switzerland.
a 6-Ph–pyridine bond, calculated torsion.
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.04.049

3580
J.-U. Peters et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3579–3580
Table 2. Influence of single substituents on the inhibitory activities of
indenopyridines
hit 1. A large activity increase was achieved by optimi-
sation of aromatic substituents and conformational
restriction, leading to a low nanomolar DPP-IV inhibi-
tor, 2k.
NH2
NH2
N
8
R
Cl
Cl
References and notes
7
1. For reviews, see: (a) Drucker, D. J. Diabetes Care 2003,
26, 2929; (b) Holst, J. J.; Orskov, C. Scand. J. Clin. Lab.
Invest. 2001, 61(Suppl. 234), 75; (c) Creutzfeldt, W. Exp.
Clin. Endocrinol. Diabetes 2001, 109(Suppl. 2), S288.
2. (a) Mojsov, S.; Weir, G. C.; Habener, J. F. J. Clin. Invest.
1987, 79, 616; (b) Drucker, D. J.; Philippe, J.; Mojsov, S.;
Chick, W. L.; Habener, J. F. Proc. Natl. Acad. Sci. U.S.A.
1987, 84, 3434; (c) Orskov, C.; Holst, J. J.; Nielsen, O. V.
Endocrinology 1988, 123, 2009.
R
IC50 (lM)
2f
2g
2h
2i
7-MeO
7-F
7-Br
0.082
0.19
0.91
0.13
0.28
8-MeO
8-Me
2j
Compound 2e was further derivatised to investigate the
influence of substitution on its inhibitory activity. The
introduction of small single substituents into the 7- or 8-
position gave generally less active compounds (2f–j,
Table 2). For instance, a 7-MeO or a 8-MeO substituent
caused a 2-fold (2f vs 2e) or a 3-fold (2i vs 2e) drop in
activity, respectively. Surprisingly, a combination of the
seemingly unfavourable 7-MeO and 8-MeO substituents
in one molecule resulted in an improved, low nanomolar
inhibitor, 2k.
€
3. Nauck, M. A.; Heimesaat, M. M.; Orskov, C.; Holst, J. J.;
Ebert, R.; Creutzfeldt, W. J. Clin. Invest. 1993, 91, 301.
4. Pauly, R. P.; Demuth, H. U.; Rosche, F.; Schmidt, J.;
White, H. A.; Lynn, F.; McIntosh, C. H.; Pederson, R. A.
Metab.: Clin. Exp. 1999, 48, 385.
5. (a) Mentlein, R.; Gallwitz, B.; Schmidt, E. Eur. J.
Biochem. 1993, 214, 829; (b) Kiefer, T. J.; McIntosh, C.
H. S.; Pederson, R. A. Endocrinology 1998, 136, 3585.
6. For reviews, see: (a) Augustyns, K.; Van der Veken, P.;
Senten, K.; Haerners, A. Expert Opin. Ther. Pat. 2003, 13,
499; (b) Drucker, D. J. Expert Opin. Invest. Drugs 2003,
12, 87; (c) Rosenblum, J. S.; Kozarich, J. W. Curr. Opin.
Chem. Biol. 2003, 7, 496.
NH2
NH2
N
7. DPP-IV inhibitors were measured for their ability to
inhibit DPP-IV mediated cleavage of Ala-Pro-7-amido-4-
trifluoromethylcoumarin in a fluorogenic assay. All com-
pounds were measured in triplicate at 5–7 concentrations
in the range of 100 lM to 100 pM. IC50 values were
calculated with a nonlinear best fit regression model. All
assays were calibrated with NVP-DPP728 as internal
standard inhibitor. NVP-DPP728 under the conditions of
the assay showed an IC50 of 15+/)4 nM (M+/)SD,
n ¼ 12) at 50 lM substrate concentration and a Ki of
11+/)3 nM determined at substrate concentration range of
10 lM to 600 lM. IC50 values of unknown compounds
were accepted when the IC50 (x) measured for NVP-
DPP728 in the assay was 11 < x < 19 nM.
MeO
MeO
Cl
Cl
2k
IC50 = 0.007µM
Aminomethylpyridines 2 were accessed as outlined in
Scheme 1: a-arylketones 3 were reacted with malono-
nitriles 4 in the presence of ammonia to give 3-cyano-
pyridines 5,10 which were subsequently reduced to
3-aminomethylpyridines 2.11 Chiral analytical HPLC
revealed that 2e was obtained as a mixture of enantio-
mers. We assume that the chirality of 2e arises from a
restricted rotation of the dichlorophenyl–pyridine bond,
caused by the steric bulk of adjacent substituents,
leading to a chiral axis and atropisomerism. Compounds
2c,d,f–k carry similar substituents and are therefore
presumably also chiral. Compounds 2c–k were tested as
(putative) racemates.
8. Peters, J.-U.; Weber, S.; Kritter, S.; Weiss, P.; Wallier, A.;
Boehringer, M.; Hennig, M.; Kuhn, B.; Loeffler, B.-M.
Bioorg. Med. Chem. Lett. 2004, 14, 1491.
€
9. Gerber, P. R.; Muller, K. J. Comput. Aided Mol. Des.
1995, 9, 251.
10. Kambe, S.; Saito, K.; Sakurai, A.; Midorikawa, H.
Synthesis 1980, 366.
11. For detailed procedures, see: (a) Boehringer, M.; Loeffler,
B.-M.; Peters, J.-U.; Riemer, C.; Weiss, P. International
Patent Application WO 03/68748, 2003; (b) Boehringer,
M.; Loeffler, B.-M.; Peters, J.-U.; Steger, M.; Weiss, P.
International Patent Application WO 03/68757, 2003.
In summary, a series of pyridine DPP-IV inhibitors 2
was derived from a weakly active pyrimidine screening
NH2
NH2
NH2
CN
CN
CN
N
N
O
a
b
+
R
R
R
R
R
R
3
4
5a- k
2a- k
Scheme 1. Reagents and conditions: (a) NH4OAc, toluene, 110 ° C, 4 h, representative yields: 5b 35%, 5c 38%, 5d 42%, 5e 18%; (b) LiAlH4, THF,
40 °C, 3 h, representative yields: 2b 6%, 2c 25%, 2d 26%, 2e 67%.