Journal of Medicinal Chemistry
Article
Zhao, G.; Mittelstadt, S. W.; Cox, B. F. Diacylglycerol acyltransferase 1
inhibition lowers serum triglycerides in the zucker fatty rat and the
hyperlipidemic hamster. J. Pharmacol. Exp. Ther. 2009, 330 (2), 526−
531. (c) Zhao, G.; Souers, A. J.; Voorbach, M.; Falls, H. D.; Droz, B.;
Brodjian, S.; Lau, Y. Y.; Iyengar, R. R.; Gao, J.; Judd, A. S.; Wagaw, S.
H.; Ravn, M. M.; Engstrom, K. M.; Lynch, J. K.; Mulhern, M. M.;
Freeman, J.; Dayton, B. D.; Wang, X.; Grihalde, N.; Fry, D.; Beno, D.
W. A.; Marsh, K. C.; Su, Z.; Diaz, G. J.; Collins, C. A.; Sham, H.; Reilly,
R. M.; Brune, M. E.; Kym, P. R. Validation of diacyl glycerolacyl-
transferase I as a novel target for the treatment of obesity and
dyslipidemia using a potent and selective small molecule inhibitor. J.
Med. Chem. 2008, 51, 380−383.
(26) (a) Nakada, Y.; Aicher, T. D.; Huerou, Y. L.; Turner, T.; Pratt,
S. A.; Gonzales, S. S.; Boyd, S. A.; Miki, H.; Yamamoto, T.; Yamaguchi,
H.; Kato, K.; Kitamura, S. Novel acyl coenzyme A (CoA):
diacylglycerol acyltransferase-1 inhibitors: synthesis and biological
activities of diacylethylenediamine derivatives. Bioorg. Med. Chem.
2010, 18, 2785−2795. (b) Yamamoto, T.; Yamaguchi, H.; Miki, H.;
Kitamura, S.; Nakada, Y.; Aicher, T. D.; Pratt, S. A.; Kato, K. A novel
coenzyme A:diacylglycerol acyltransferase 1 inhibitor stimulates lipid
metabolism in muscle and lowers weight in animal models of obesity.
Eur. J. Pharmacol. 2011, 650, 663−672.
(27) (a) Yamamoto, T.; Yamaguchi, H.; Miki, H.; Shimada, M.;
Nakada, Y.; Ogino, M.; Asano, K.; Aoki, K.; Tamura, N.; Masago, M.;
Kato, K. Coenzyme A: diacylglycerol acyltransferase 1 inhibitor
ameliorates obesity, liver steatosis, and lipid metabolism abnormality in
KKAy mice fed high-fat or high-carbohydrate diets. Eur. J. Pharmacol.
2010, 640, 243−249. (b) Nakada, Y.; Ogino, M.; Asano, K.; Aoki, K.;
Miki, H.; Yamamoto, T.; Kato, K.; Masago, M.; Tamura, N.; Shimada,
M. Novel acyl coenzyme A:diacylglycerol acyltransferase 1 inhib-
itorssynthesis and biological activities of N-(substituted heteroaryl)-
4-(substituted phenyl)-4-oxobutanamides. Chem. Pharm. Bull. 2010,
58 (5), 673−679.
(28) Motiwala, H.; Kandre, S.; Birar, V.; Kadam, K. S.; Rodge, A.;
Jadhav, R. D.; Reddy, M. M. K.; Brahma, M. K.; Deshmukh, N. J.;
Dixit, A.; Doshi, L.; Gupte, A.; Gangopadhyay, A. K.; Vishwakarma, R.
A.; Srinivasan, S.; Sharma, M.; Nemmani, K. V. S.; Sharma, R.
Exploration of pyridine containing heteroaryl analogs of biaryl ureas as
DGAT1 inhibitors. Bioorg. Med. Chem. Lett. 2011, 21, 5812−5817.
(29) Yun, W.; Ahmad, M.; Chen, Y.; Gillespie, P.; Conde-Knape, K.;
Kazmer, S.; Li, S.; Qian, Y.; Taub, R.; Wertheimer, S. J.; Whittard, T.;
Bolin, D. Discovery and optimization of 2-phenyloxazole derivatives as
diacylglycerol acyltransferase-1 inhibitors. Bioorg. Med. Chem. Lett.
2011, 21, 7205−7209.
(30) Dow, R. L.; Andrews, M.; Aspnes, G. E.; Balan, G.; Gibbs, M.;
Guzman-Perez, A.; Karki, K.; LaPerle, J. L.; Li, J.-C.; Litchfield, J.;
Munchhof, M. J.; Perreault, C.; Patel, L. Design and synthesis of
potent, orally-active DGAT-1 inhibitors containing a dioxino[2,3-
d]pyrimidine core. Bioorg. Med. Chem. Lett. 2011, 21, 6122−6125.
(31) Qian, Y.; Wertheimer, S. J.; Ahmad, M.; Cheung, A. W.-H.;
Firooznia, F.; Hamilton, M. H.; Hayden, S.; Li, S.; Marcopulos, N.;
McDermott, L.; Tan, J.; Yun, W.; Guo, L.; Pamidimukkala, A.; Chen,
Y.; Huang, K.-S.; Ramsey, G. B.; Whittard, T.; Conde-Knape, K.; Taub,
R.; Rondinone, C. M.; Tilley, J.; Bolin, D. Discovery of orally active
carboxylic acid derivatives of 2-phenyl-5-trifluoromethyloxazole-4-
carboxamide as potent diacylglycerol acyltransferase-1 inhibitors for
the potential treatment of obesity and diabetes. J. Med. Chem. 2011,
54, 2433−2446.
(32) Dow, R. L.; Li, J.-C.; Pence, M. P.; Gibbs, M.; LaPerle, J. L.;
Litchfield, J.; Piotrowski, D. W.; Munchhof, M. J.; Manion, T. B.;
Zavadoski, W. J.; Walker, G. S.; McPherson, R. K.; Tapley, S.;
Sugarman, E.; Guzman-Perez, A.; DaSilva-Jardine, P. Discovery of PF-
04620110, a potent, selective, and orally bioavailable inhibitor of
DGAT-1. ACS Med. Chem. Lett. 2011, 2, 407−412.
(34) Mougenot, P.; Namane, C.; Fett, E.; Camy, F.; Dadji-Faihun, R.;
Langot, G.; Monseau, C.; Onofri, B.; Pacquet, F.; Pascal, C.; Crespin,
O.; Ben-Hassine, M.; Ragot, J.-L.; Van-Pham, T.; Philippo, C.;
Chatelain-Egger, F.; Peron, P.; Le Bail, J.-C.; Guillot, E.; Chamiot-
Clerc, P.; Chabanaud, M.-A.; Pruniaux, M.-P.; Schmidt, F.; Venier, O.;
Nicolai, E.; Viviani, F. Thiadiazoles as new inhibitors of diacylglycerol
acyltransferase type 1. Bioorg. Med. Chem. Lett. 2012, 22, 2497−2502.
(35) McCoull, W.; Addie, M. S.; Birch, A. M.; Birtles, S.; Buckett, L.
K.; Butlin, R. J.; Bowker, S. S.; Boyd, S.; Chapman, S.; Davies, R. D.
M.; Donald, C. S.; Green, C. P.; Jenner, C.; Kemmitt, P. D.; Leach, A.
G.; Moody, G. C.; Gutierrez, P. M.; Newcombe, N. J.; Nowak, T.;
Packer, M. J.; Plowright, A. T.; Revill, J.; Schofield, P.; Sheldon, C.;
Stokes, S.; Turnbull, A. V.; Wang, S. J. Y.; Whalley, D. P.; Wood, J. M.
Identification, optimisation and in vivo evaluation of oxadiazole
DGAT-1 inhibitors for the treatment of obesity and diabetes. Bioorg.
Med. Chem. Lett. 2012, 22, 3873−3878.
(36) Lee, K.; Goo, J.-I.; Jung, H. Y.; Kim, M.; Boovanahalli, S. K.;
Park, H. R.; Kim, M.-O.; Kim, D.-H.; Lee, H. S.; Choi, Y. Discovery of
a novel series of benzimidazole derivatives as diacylglycerol
acyltransferase inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 7456−
7460.
(37) (a) Denison, H.; Nilsson, C.; Kujacic, M.; Lofgren, L.; Karlsson,
C.; Knutsson, M.; Eriksson, J. W. Proof of mechanism for the DGAT1
inhibitor AZD7687: results from a first-time-in-human single-dose
study. Diabetes, Obes. Metab. 2012, 1−8. (b) Barlind, J. G.; Bauer, U.
A.; Birch, A. M.; Birtles, S.; Buckett, L. K.; Butlin, R. J.; Davies, R. D.
M.; Eriksson, J. W.; Hammond, C. D.; Hovland, R.; Johannesson, P.;
Johansson, M. J.; Kemmitt, P. D.; Lindmark, B. T.; Gutierrez, P. M.;
Noeske, T. A.; Nordin, A.; O’Donnell, C. J.; Petersson, A. U.; Redzic,
A.; Turnbull, A. V.; Vinblad, J. Design and optimization of
pyrazinecarboxamide-based inhibitors of diacylglycerol acyltransferase
1 (DGAT1) leading to a clinical candidate dimethylpyrazine-
carboxamide phenylcyclohexylacetic acid (AZD7687). J. Med. Chem.
2012, 55, 10610−10629.
(38) Yeh, V. S. C.; Beno, D. W. A.; Brodjian, S.; Brune, M. E.; Cullen,
S. C.; Dayton, B. D.; Dhaon, M. K.; Falls, H. D.; Gao, J.; Grihalde, N.;
Hajduk, P.; Hansen, T. M.; Judd, A. S.; King, A. J.; Klix, R. C.; Larson,
K. J.; Lau, Y. Y.; Marsh, K. C.; Mittlestadt, S. W.; Plata, D.; Rozema, M.
J.; Segreti, J. A.; Stoner, E. J.; Voorbach, M. J.; Wang, X.; Xin, X.; Zhao,
G.; Collins, C. A.; Cox, B. F.; Reilly, R. M.; Kym, P. R.; Souers, A. J.
Identification and preliminary characterization of a potent, safe, and
orally efficacious inhibitor of acyl-CoA:diacylglycerol acyltransferase 1.
J. Med. Chem. 2012, 55, 1751−1757.
(39) Serrano-Wu, M.; Coppola, G. M.; Gong, Y.; Neubert, A. D.;
Chatelain, R.; Clairmont, K. B.; Commerford, R.; Cosker, T.; Daniels,
T.; Hou, Y.; Jain, M.; Juedes, M.; Li, L.; Mullarkey, T.; Rocheford, E.;
Sung, M. J.; Tyler, A.; Yang, Q.; Yoon, T.; Hubbard, B. K. Intestinally
targeted diacylglycerol acyltransferase 1 (DGAT1) inhibitors robustly
suppress postprandial triglycerides. ACS Med. Chem. Lett. 2012, 3,
411−415.
(40) Plowright, A. T.; Barton, P.; Bennett, S.; Birch, A. M.; Birtles, S.;
Buckett, L. K.; Butlin, R. J.; Davies, R. D. M.; Ertan, A.; Gutierrez, P.
M.; Kemmitt, P. D.; Leach, A. G.; Svensson, P. H.; Turnbull, A. V.;
Waring, M. J. Design and synthesis of a novel series of cyclo-
hexyloxypyridyl derivatives as inhibitors of diacylglycerol acyltransfer-
ase 1. Med. Chem. Commun. 2013, 4, 151−158.
(41) Fox, B. M.; Furukawa, N.; Hao, X.; Iio, K.; Inaba, T.; Jackson, S.
M.; Kayser, F.; Labelle, M.; Li, K.; Matsui, T.; McMinn, D.; Ogawa, N.;
Rubenstein, S. M.; Sagawa, S.; Sugimoto, K.; Suzuki, M.; Tanaka, M.;
Ye, G.; Yoshida, A.; Zhang, J. Fused bicyclic nitrogen-containing
heterocycles. Patent WO 2004047755, 2004.
(42) DeVita, R. J.; Pinto, S. Current status of the research and
development of diacylcglycerol O-acyltransferase 1 (DGAT1)
inhibitors. J. Med. Chem. 2013, 56, 9820−9825.
(43) Maciejewski, B. J.; LaPerle, J. L.; Chen, D.; Ghosh, A.;
Zavadoski, W. J.; McDonald, T. S.; Manion, T. B.; Mather, D.;
Patterson, T. A.; Hanna, M.; Watkins, S.; Gibbs, E. M.; Calle, R. A.;
Steppan, C. M. Pharmacological inhibition to examine the role of
(33) Bali, U.; Barba, O.; Dawson, G.; Gattrell, W. T.; Horswill, J. G.;
Pan, D. A.; Procter, M. J.; Rasamison, C. M.; Smith, C. P. S.; Taylor-
Warne, A.; Wong-Kai-In, P. Design and synthesis of potent carboxylic
acid DGAT1 inhibitors with high cell permeability. Bioorg. Med. Chem.
Lett. 2012, 22, 824−828.
3482
dx.doi.org/10.1021/jm500135c | J. Med. Chem. 2014, 57, 3464−3483