Free fatty acid receptor 1 (FFA1/GPR40) agonists: Mesylpropoxy appendage lowers lipophilicity and improves ADME properties

Journal of Medicinal Chemistry

Volumn 55, Issue 14, 2012, Pages 6624-6628

  Christiansen, Elisabeth ^a   Due Hansen, Maria E ^a   Urban, Christian ^b   Grundmann, Manuel ^c   Schröder, Ralf ^c   Hudson, Brian D ^d   Milligan, Graeme ^d   Cawthorne, Michael A ^e   Kostenis, Evi ^c   Kassack, Matthias U ^b   Ulven, Trond ^a  

^a UNIVERSITY OF SOUTHERN DENMARK   (Denmark)

^b HEINRICH HEINE UNIVERSITY   (Germany)

^c UNIVERSITY OF BONN   (Germany)

^d UNIVERSITY OF GLASGOW   (United Kingdom)

^e UNIVERSITY OF BUCKINGHAM   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

G PROTEIN COUPLED RECEPTOR 40; TAK 875; TUG 469; UNCLASSIFIED DRUG;

AREA UNDER THE CURVE; ARTICLE; DRUG ABSORPTION; DRUG DISTRIBUTION; DRUG EFFECT; DRUG EXCRETION; DRUG METABOLISM; DRUG STRUCTURE; LIPOPHILICITY; MAXIMUM PLASMA CONCENTRATION; NON INSULIN DEPENDENT DIABETES MELLITUS; TIME TO MAXIMUM PLASMA CONCENTRATION;

ABSORPTION; BENZENE; HEK293 CELLS; HUMANS; HYDROPHOBIC AND HYDROPHILIC INTERACTIONS; RECEPTORS, G-PROTEIN-COUPLED; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84864228135     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm3002026     Document Type: Article

References (28)

1. Leeson, P. D.; Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry Nature Rev. Drug Discovery 2007, 6, 881-890
2. Hann, M. M. Molecular obesity, potency and other addictions in drug discovery MedChemCommun 2011, 2, 349-355
3. Waring, M. J. Lipophilicity in drug discovery Expert Opin. Drug Discovery 2010, 5, 235-248
4. Gleeson, M. P. Generation of a set of simple, interpretable ADMET rules of thumb J. Med. Chem. 2008, 51, 817-834
5. Walters, W. P.; Green, J.; Weiss, J. R.; Murcko, M. A. What Do Medicinal Chemists Actually Make? A 50-Year Retrospective J. Med. Chem. 2011, 54, 6405-6416
6. Tarcsay, A.; Nyiri, K.; Keseru, G. M. The Impact of Lipophilic Efficiency on Compound Quality J. Med. Chem. 2012, 55, 1252-1260
7. Keseru, G. M.; Makara, G. M. The influence of lead discovery strategies on the properties of drug candidates Nature Rev. Drug Discovery 2009, 8, 203-212
8. Hopkins, A. L.; Groom, C. R.; Alex, A. Ligand efficiency: a useful metric for lead selection Drug Discovery Today 2004, 9, 430-431
9. Itoh, Y.; Kawamata, Y.; Harada, M.; Kobayashi, M.; Fujii, R.; Fukusumi, S.; Ogi, K.; Hosoya, M.; Tanaka, Y.; Uejima, H.; Tanaka, H.; Maruyama, M.; Satoh, R.; Okubo, S.; Kizawa, H.; Komatsu, H.; Matsumura, F.; Noguchi, Y.; Shinobara, T.; Hinuma, S.; Fujisawa, Y.; Fujino, M. Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40 Nature 2003, 422, 173-176
10. Briscoe, C. P.; Tadayyon, M.; Andrews, J. L.; Benson, W. G.; Chambers, J. K.; Eilert, M. M.; Ellis, C.; Elshourbagy, N. A.; Goetz, A. S.; Minnick, D. T.; Murdock, P. R.; Sauls, H. R.; Shabon, U.; Spinage, L. D.; Strum, J. C.; Szekeres, P. G.; Tan, K. B.; Way, J. M.; Ignar, D. M.; Wilson, S.; Muir, A. I. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids J. Biol. Chem. 2003, 278, 11303-11311
11. Kotarsky, K.; Nilsson, N. E.; Flodgren, E.; Owman, C.; Olde, B. A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs Biochem. Biophys. Res. Commun. 2003, 301, 406-410
12. Briscoe, C. P.; Peat, A. J.; McKeown, S. C.; Corbett, D. F.; Goetz, A. S.; Littleton, T. R.; McCoy, D. C.; Kenakin, T. P.; Andrews, J. L.; Ammala, C.; Fornwald, J. A.; Ignar, D. M.; Jenkinson, S. Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules Br. J. Pharmacol. 2006, 148, 619-628
13. Garrido, D. M.; Corbett, D. F.; Dwornik, K. A.; Goetz, A. S.; Littleton, T. R.; McKeown, S. C.; Mills, W. Y.; Smalley, T. L.; Briscoe, C. P.; Peat, A. J. Synthesis and activity of small molecule GPR40 agonists Bioorg. Med. Chem. Lett. 2006, 16, 1840-1845
14. McKeown, S. C.; Corbett, D. F.; Goetz, A. S.; Littleton, T. R.; Bigham, E.; Briscoe, C. P.; Peat, A. J.; Watson, S. P.; Hickey, D. M. B. Solid phase synthesis and SAR of small molecule agonists for the GPR40 receptor Bioorg. Med. Chem. Lett. 2007, 17, 1584-1589
15. Christiansen, E.; Urban, C.; Merten, N.; Liebscher, K.; Karlsen, K. K.; Hamacher, A.; Spinrath, A.; Bond, A. D.; Drewke, C.; Ullrich, S.; Kassack, M. U.; Kostenis, E.; Ulven, T. Discovery of potent and selective agonists for the free fatty acid receptor 1 (FFA1/GPR40), a potential target for the treatment of type II diabetes J. Med. Chem. 2008, 51, 7061-7064
16. Tan, C. P.; Feng, Y.; Zhou, Y. P.; Eiermann, G. J.; Petrov, A.; Zhou, C. Y.; Lin, S. N.; Salituro, G.; Meinke, P.; Mosley, R.; Akiyama, T. E.; Einstein, M.; Kumar, S.; Berger, J. P.; Mills, S. G.; Thornberry, N. A.; Yang, L. H.; Howard, A. D. Selective small-molecule agonists of G protein-coupled receptor 40 promote glucose-dependent insulin secretion and reduce blood glucose in mice Diabetes 2008, 57, 2211-2219
17. Zhou, C. Y.; Tang, C.; Chang, E.; Ge, M.; Lin, S. N.; Cline, E.; Tan, C. P.; Feng, Y.; Zhou, Y. P.; Eiermann, G. J.; Petrov, A.; Salituro, G.; Meinke, P.; Mosley, R.; Akiyama, T. E.; Einstein, M.; Kumar, S.; Berger, J.; Howard, A. D.; Thornberry, N.; Mills, S. G.; Yang, L. H. Discovery of 5-aryloxy-2,4- thiazolidinediones as potent GPR40 agonists Bioorg. Med. Chem. Lett. 2010, 20, 1298-1301
18. Negoro, N.; Sasaki, S.; Mikami, S.; Ito, M.; Suzuki, M.; Tsujihata, Y.; Ito, R.; Harada, A.; Takeuchi, K.; Suzuki, N.; Miyazaki, J.; Santou, T.; Odani, T.; Kanzaki, N.; Funami, M.; Tanaka, T.; Kogame, A.; Matsunaga, S.; Yasuma, T.; Momose, Y. Discovery of TAK-875: A Potent, Selective, and Orally Bioavailable GPR40 Agonist ACS Med. Chem. Lett. 2010, 1, 290-294
19. Christiansen, E.; Due-Hansen, M. E.; Urban, C.; Merten, N.; Pfleiderer, M.; Karlsen, K. K.; Rasmussen, S. S.; Steensgaard, M.; Hamacher, A.; Schmidt, J.; Drewke, C.; Petersen, R. K.; Kristiansen, K.; Ullrich, S.; Kostenis, E.; Kassack, M. U.; Ulven, T. Structure-activity study of dihydrocinnamic acids and discovery of the potent FFA1 (GPR40) agonist TUG-469 ACS Med. Chem. Lett. 2010, 1, 345-349
20. Sasaki, S.; Kitamura, S.; Negoro, N.; Suzuki, M.; Tsujihata, Y.; Suzuki, N.; Santou, T.; Kanzaki, N.; Harada, M.; Tanaka, Y.; Kobayashi, M.; Tada, N.; Funami, M.; Tanaka, T.; Yamamoto, Y.; Fukatsu, K.; Yasuma, T.; Momose, Y. Design, Synthesis, and Biological Activity of Potent and Orally Available G Protein-Coupled Receptor 40 Agonists J. Med. Chem. 2011, 54, 1365-1378
21. Walsh, S. P.; Severino, A.; Zhou, C. Y.; He, J. F.; Liang, G. B.; Tan, C. P.; Cao, J.; Eiermann, G. J.; Xu, L.; Salituro, G.; Howard, A. D.; Mills, S. G.; Yang, L. H. 3-Substituted 3-(4-aryloxyaryl)-propanoic acids as GPR40 agonists Bioorg. Med. Chem. Lett. 2011, 21, 3390-3394
22. Christiansen, E.; Urban, C.; Grundmann, M.; Due-Hansen, M. E.; Hagesaether, E.; Schmidt, J.; Pardo, L.; Ullrich, S.; Kostenis, E.; Kassack, M. U.; Ulven, T. Identification of a potent and selective free fatty acid receptor 1 (FFA1/GPR40) agonist with favorable physicochemical and in vitro ADME properties J. Med. Chem. 2011, 54, 6691-6703
23. Houze, J. B.; Zhu, L.; Sun, Y.; Akerman, M.; Qiu, W.; Zhang, A. J.; Sharma, R.; Schmitt, M.; Wang, Y.; Liu, J.; Liu, J.; Medina, J. C.; Reagan, J. D.; Luo, J.; Tonn, G.; Zhang, J.; Lu, J. Y.-L.; Chen, M.; Lopez, E.; Nguyen, K.; Yang, L.; Tang, L.; Tian, H.; Shuttleworth, S. J.; Lin, D. C. H. AMG 837: A Potent, Orally Bioavailable GPR40 Agonist Bioorg. Med. Chem. Lett. 2012, 22, 1267-1270
24. Negoro, N.; Sasaki, S.; Ito, M.; Kitamura, S.; Tsujihata, Y.; Ito, R.; Suzuki, M.; Takeuchi, K.; Suzuki, N.; Miyazaki, J.; Santou, T.; Odani, T.; Kanzaki, N.; Funami, M.; Tanaka, T.; Yasuma, T.; Momose, Y. Identification of Fused-Ring Alkanoic Acids with Improved Pharmacokinetic Profiles that Act as G Protein-Coupled Receptor 40/Free Fatty Acid Recptor 1 Agonists J. Med. Chem. 2012, 55, 1538-1552
25. Mikami, S.; Kitamura, S.; Negoro, N.; Sasaki, S.; Suzuki, M.; Tsujihata, Y.; Miyazaki, T.; Ito, R.; Suzuki, N.; Miyazaki, J.; Santou, T.; Kanzaki, N.; Funami, M.; Tanaka, T.; Yasuma, T.; Momose, Y. Discovery of Phenylpropanoic Acid Derivatives Containing Polar Functionalities as Potent and Orally Bioavailable G Protein-Coupled Receptor 40 Agonists for the Treatment of Type 2 Diabetes J. Med. Chem. 2012, 55, 3756-3776
26. Negoro, N.; Sasaki, S.; Mikami, S.; Ito, M.; Tsujihata, Y.; Ito, R.; Suzuki, M.; Takeuchi, K.; Suzuki, N.; Miyazaki, J.; Santou, T.; Odani, T.; Kanzaki, N.; Funami, M.; Morohashi, A.; Nonaka, M.; Matsunaga, S.; Yasuma, T.; Momose, Y. Optimization of (2,3-Dihydro-1-benzofuran-3-yl)acetic Acids: Discovery of a Non-Free Fatty Acid-Like, Highly Bioavailable G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonist as a Glucose-Dependent Insulinotropic Agent J. Med. Chem. 2012, 55, 3960-3974
27. Ashton, W. T.; Sisco, R. M.; Yang, Y. T.; Lo, J. L.; Yudkovitz, J. B.; Cheng, K.; Goulet, M. T. Substituted indole-5-carboxamides and -acetamides as potent nonpeptide GnRH receptor antagonists Bioorg. Med. Chem. Lett. 2001, 11, 1723-1726
28. Schroder, R.; Janssen, N.; Schmidt, J.; Kebig, A.; Merten, N.; Hennen, S.; Muller, A.; Blattermann, S.; Mohr-Andra, M.; Zahn, S.; Wenzel, J.; Smith, N. J.; Gomeza, J.; Drewke, C.; Milligan, G.; Mohr, K.; Kostenis, E. Deconvolution of complex G protein-coupled receptor signaling in live cells using dynamic mass redistribution measurements Nature Biotechnol. 2010, 28, 943-950