DiscoVery of PSN-GK1
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 14 4345
(19) Dunten, P.; Swain, A.; Kammlott, U.; Crowther, R.; Lukacs, C. M.;
Levin, W.; Reik, L.; Grimsby, J.; Corbett, W. L.; Magnuson, M. A.;
Matschinsky, F. M.; Grippo, J. F. Crystal structure of human liver
glucokinase bound to a small molecule allosteric activator. In
Glucokinase and Glycemic Disease: From Basics to NoVel Thera-
peutics; Matschinsky, F. M., Magnuson, M. A., Eds.; Karger: Basel,
Switzerland, 2004; pp 145-154.
(20) Coope, G. J.; Atkinson, A. M.; Allott, C.; McKerrecher, D.; Johnstone,
C.; Pike, K. G.; Holme, P. C.; Vertigan, H.; Gill, D.; Coghlan, M. P.;
Leighton, B. Predictive blood glucose lowering efficacy by glucokinase
activators in high fat fed female Zucker rats. Br. J. Pharmacol. 2006,
149, 328–335.
(21) Fyfe, M. C. T.; White, J.; Taylor, A.; Chatfield, R.; Wargent, E.; Printz,
R. L.; Sulpice, T.; McCormack, J. G.; Procter, M. J.; Reynet, C.;
Widdowson, P. S.; Wong-kai-in, P. Glucokinase activator PSN-GK1
displays enhanced antihyperglycemic and insulinotropic actions.
Diabetologia 2007, 50, 1277–1287.
(22) Grimsby, J. Antidiabetic Effects of Glucokinase Activators: From
Benchside to Bedside. Keystone Symposium. Diabetes Mellitus, Insulin
Action and Resistance, Keystone, CO, 22-27 January 2008; Abstract
151.
the crystal structure of 13. Finally, we would like to acknowl-
edge Gattefosse´ (Gennevilliers, France) for generously supplying
us with Gelucire 44/14.
Supporting Information Available: Further experimental details
and crystallographic data. This material is available free of charge
References
(1) Moller, D. E. New drug targets for type 2 diabetes and the metabolic
syndrome. Nature 2001, 414, 821–827.
(2) Gershell, L. Type 2 diabetes market. Nature ReV. Drug DiscoVery
2005, 4, 367–368.
(3) Bell, D. S. H. A comparison of agents used to manage type 2 diabetes
mellitus: Need for reappraisal of traditional approaches. Treat.
Endocrinol. 2004, 3, 67–76.
(4) Sarabu, R.; Tilley, J. Recent advances in therapeutic approaches to
type 2 diabetes. Annu. Rep. Med. Chem. 2005, 40, 167–181.
(5) Sarabu, R.; Grimsby, J. Targeting glucokinase activation for the
treatment of type 2 diabetes: A status review. Curr. Opin. Drug
DiscoVery DeV. 2005, 8, 631–637.
(6) Kietzmann, T.; Ganjam, G. K. Glucokinase: old enzyme, new target.
Expert Opin. Ther. Pat. 2005, 15, 705–713.
(7) Guertin, K. R.; Grimsby, J. Small molecule glucokinase activators as
glucose lowering agents: a new paradigm for diabetes therapy. Curr.
Med. Chem. 2006, 13, 1839–1843.
(23) Daniewski, A. R.; Liu, W.; Radinov, R. N. Process for the preparation
of a glucokinase activator. International Patent WO 2007/115968,
2007.
(24) Corbett, W. L.; Sarabu, R.; Sidduri, A. Trans olefinic glucokinase
activators. International Patent WO 2001/044216, 2001.
(25) Karminski-Zamola, G.; Bajic, M. Synthesis of (5-styryl-2-thienyl)phe-
nylacrylic Acids. Heterocycles 1985, 23, 1497–1501.
(26) See Supporting Information.
(27) Bizzarro, F. T.; Corbett, W. L.; Focella, A.; Grippo, J. F.; Haynes,
N.-E.; Holland, G. W.; Kester, R. F.; Mahaney, P. E.; Sarabu, R.
Glucokinase activators. International Patent WO 2000/058293, 2000.
(28) Van de Waterbeemd, H.; Smith, D. A.; Beaumont, K.; Walker, D. K.
Property-based design: Optimization of drug absorption and pharma-
cokinetics. J. Med. Chem. 2001, 44, 1313–1333.
(29) Corbett, W. L.; Grimsby, J. S.; Haynes, N. E.; Kester, R. F.; Mahaney,
P. E.; Racha, J. K.; Sarabu, R.; Wang, K. Substituted phenylacetamides
and their use as glucokinase activators. International Patent WO 2003/
095438, 2003.
(30) Heuser, S.; Barrett, D. G.; Berg, M.; Bonnier, B.; Kahl, A.; Luz De
La Puente, M.; Oram, N.; Riedl, R.; Roettig, U.; Sanz Gil, G.; Seger,
E.; Steggles, D. J.; Wanner, J.; Weichert, A. G. Synthesis of novel
cyclopropylic sulfones and sulfonamides acting as glucokinase activa-
tors. Tetrahedron Lett. 2006, 47, 2675–2678.
(31) Willmann, S.; Schmitt, W.; Keldenich, J.; Lippert, J.; Dressman, J. B.
A physiological model for the estimation of the fraction dose absorbed
in humans. J. Med. Chem. 2004, 47, 4022–4031.
(32) Haigh, D.; Birrell, H. C.; Cantello, B. C. C.; Hindley, R. M.;
Ramaswamy, A.; Rami, H. K.; Stevens, N. C. Non-thiazolidinedione
antihyperglycemic agents. Part 4: Synthesis of (()-, (R)-(+)-, and (S)-
(-)-enantiomers of 2-oxy-3-arylpropanoic acids. Tetrahedron: Asym-
metry 1999, 10, 1335–1351.
(33) Briner, P. H.; Fyfe, M. C. T.; Madeley, J. P.; Murray, P. J.; Procter,
M. J.; Spindler, F. Enantioselective process. International Patent WO
2006/016178, 2006.
(8) Johnson, T. O.; Humphries, P. S. Glucokinase activators for the
treatment of type 2 diabetes. Annu. Rep. Med. Chem. 2006, 41, 141–
154.
(9) Grimsby, J.; Sarabu, R.; Corbett, W. L.; Haynes, N.-E.; Bizzarro, F. T.;
Coffey, J. W.; Guertin, K. R.; Hilliard, D. W.; Kester, R. F.; Mahaney,
P. E.; Marcus, L.; Qi, L.; Spence, C. L.; Tengi, J.; Magnuson, M. A.;
Chu, C. A.; Dvorozniak, M. T.; Matschinsky, F. M.; Grippo, J. F.
Allosteric activators of glucokinase: potential role in diabetes therapy.
Science 2003, 301, 370–373.
(10) Bebernitz, G. R. Substituted (thiazol-2-yl)-amide or sulfonamide as
glucokinase activators useful in the treatment of type 2 diabetes.
International Patent WO 2004/050645, 2004.
(11) Castelhano, A. L.; Dong, H.; Fyfe, M. C. T.; Gardner, L. S.;
Kamikozawa, Y.; Kurabayashi, S.; Nawano, M.; Ohashi, R.; Procter,
M. J.; Qiu, L.; Rasamison, C. M.; Schofield, K. L.; Shah, V. K.; Ueta,
K.; Williams, G. M.; Witter, D.; Yasuda, K. Glucokinase-activating
ureas. Bioorg. Med. Chem. Lett. 2005, 15, 1501–1504.
(12) Efanov, A. M.; Barrett, D. G.; Brenner, M. B.; Briggs, S. L.; Delaunois,
A.; Durbin, J. D.; Giese, U.; Guo, H.; Radloff, M.; Gil, G. S.; Sewing,
S.; Wang, Y.; Weichert, A.; Zaliani, A.; Gromada, J. A novel
glucokinase activator modulates pancreatic islet and hepatocyte
function. Endocrinology 2005, 146, 3696–3701.
(13) Murray, A.; Lau, J.; Jeppesen, L.; Vedsø, P.; Ankersen, M.; Lundbeck,
J. M.; Kristiansen, M.; Valcarce-Lope´z, M. C.; Polisetti, D. R.;
Subramanian, G.; Andrews, R. C.; Christen, D. P.; Cooper, J. T.;
Santhosh, K. C. Heteroaryl-ureas and their use as glucokinase
activators. International Patent WO 2005/066145, 2005.
(14) McKerrecher, D.; Allen, J. V.; Caulkett, P. W. R.; Donald, C. S.;
Fenwick, M. L.; Grange, E.; Johnson, K. M.; Johnstone, C.; Jones,
C. D.; Pike, K. G.; Rayner, J. W.; Walker, R. P. Design of a potent,
soluble glucokinase activator with excellent in vivo efficacy. Bioorg.
Med. Chem. Lett. 2006, 16, 2705–2709.
(15) Bian, H.; Dudash, J.; Patel, M.; Rybczynski, P.; Zhang, Y. Dihy-
droisoindolones as allosteric modulators of glucokinase. International
Patent WO 2007/053662, 2007.
(16) Aicher, T. D.; Boyd, S. A.; Chicarelli, M. J.; Condroski, K. R.; Hinklin,
R. J.; Singh, A.; Turner, T. M.; Rustam, F. G. Glucokinase activators.
International Patent WO 2007/089512, 2007.
(34) Guengerich, F. P.; MacDonald, J. S. Applying mechanisms of chemical
toxicity to predict drug safety. Chem. Res. Toxicol. 2007, 20, 344–
369.
(35) Hobbs, D. C.; Twomey, T. M. Metabolism of sudoxicam by the rat,
dog, and monkey. Drug Metab. Dispos. 1977, 5, 75–81.
(36) Onderwater, R. C. A.; Commandeur, J. N. M.; Menge, W. M. P. B.;
Vermeulen, N. P. E. Activation of microsomal glutathione S-transferase
and inhibition of cytochrome P450 1A1 activity as a model system
for detecting protein alkylation by thiourea-containing compounds in
rat liver microsomes. Chem. Res. Toxicol. 1999, 12, 396–402.
(37) Briner, P. H.; Fyfe, M. C. T.; Martin, P.; Murray, P. J.; Naud, F.;
Procter, M. J. Practical synthesis of 2-amino-5-fluorothiazole hydro-
chloride. Org. Process Res. DeV. 2006, 10, 346–348.
(38) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.;
Gleason, J. L. Pseudoephedrine as a practical chiral auxiliary for the
synthesis of highly enantiomerically enriched carboxylic acids, alco-
hols, aldehydes, and ketones. J. Am. Chem. Soc. 1997, 119, 6496–6511.
(17) Cheruvallath, Z.; Feng, J.; Guntupalli, P.; Gwaltney, S. L.; Kaldor,
S. W.; Miura, J.; Sabat, M.; Tang, M.; Wolgast, B. Glucokinase
activators. International Patent WO 2007/104034, 2007.
(18) Kamata, K.; Mitsuya, M.; Nishimura, T.; Eiki, J.-I.; Nagata, Y.
Structural basis for allosteric regulation of the monomeric allosteric
enzyme human glucokinase. Structure 2004, 12, 429–438.
JM8003202