Discovery and Structure-Guided Optimization of Diarylmethanesulfonamide Disrupters of Glucokinase-Glucokinase Regulatory Protein (GK-GKRP) Binding: Strategic Use of a N → S (nN → σ∗ S-X) Interaction for Conformational Constraint

Journal of Medicinal Chemistry

Volumn 58, Issue 24, 2015, Pages 9663-9679

  Pennington, Lewis D ^a,b   Bartberger, Michael D ^a   Croghan, Michael D ^a   Andrews, Kristin L ^a   Ashton, Kate S ^a   Bourbeau, Matthew P ^a   Chen, Jie ^a   Chmait, Samer ^a   Cupples, Rod ^a   Fotsch, Christopher ^a   Helmering, Joan ^a   Hong, Fang Tsao ^a   Hungate, Randall W ^a   Jordan, Steven R ^a   Kong, Ke ^a   Liu, Longbin ^a   Michelsen, Klaus ^a   Moyer, Carolyn ^a   Nishimura, Nobuko ^a   Norman, Mark H ^a   Reichelt, Andreas ^a   Siegmund, Aaron C ^a   Sivits, Glenn ^a   Tadesse, Seifu ^a   Tegley, Christopher M ^a   Van, Gwyneth ^a   Yang, Kevin C ^a   Yao, Guomin ^a   Zhang, Jiandong ^a   Lloyd, David J ^a   Hale, Clarence ^a   St Jean, David J ^a   more..

^a AMGEN INC   (United States)

^b Alkermes   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIDIABETIC AGENT; AROMATIC COMPOUND; DIARYLMETHANESULFONAMIDE DERIVATIVE; GLUCOKINASE; GLUCOKINASE REGULATORY PROTEIN; GLUCOSE; N [(2 AMINO 5 CHLORO 3 FLUORO 4 PYRIDINYL)[7 [4 (1 HYDROXY 1 METHYLETHYL) 2 PYRIDINYL] 1 BENZOTHIOPHEN 2 YL]METHYL]CYCLOPROPANESULFONAMIDE; N [(2 AMINO 5 CHLORO 4 PYRIMIDINYL)[7 [4 (1 HYDROXY 1 METHYLETHYL) 2 PYRIDINYL] 1 BENZOTHIOPHEN 2 YL]METHYL]CYCLOPROPANESULFONAMIDE; N [(2 CHLOROPHENYL)[7 [4 (2,2,2 TRIFLUORO 1 HYDROXY 1 METHYLETHYL) 2 PYRIDINYL] 1 BENZOTHIOPHEN 2 YL]METHYL]CYCLOPROPANESULFONAMIDE; N [1 BENZOFURAN 2 YL(PHENYL)METHYL] 3,4 DIHYDRO 2H 1,5 BENZODIOXEPINE 7 SULFONAMIDE; N [1 BENZOTHIOPHEN 2 YL(2 CHLOROPHENYL)METHYL] 3,4 DIHYDRO 2H 1,5 BENZODIOXEPINE 7 SULFONAMIDE; NITROGEN; REGULATOR PROTEIN; SULFONAMIDE; SULFUR; UNCLASSIFIED DRUG; GCKR PROTEIN, HUMAN; GLUCOSE BLOOD LEVEL; N-((2-AMINO-5-CHLORO-3-FLUORO-4-PYRIDINYL)(7-(4-(1-HYDROXY-1-METHYLETHYL)-2-PYRIDINYL)-1-BENZOTHIOPHEN-2-YL)METHYL)CYCLOPROPANESULFONAMIDE; PROTEIN BINDING; SIGNAL TRANSDUCING ADAPTOR PROTEIN; THIOPHENE DERIVATIVE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CELL NUCLEUS; CONFORMATION; CONTROLLED STUDY; CRYSTAL STRUCTURE; CYTOPLASM; DRUG CLEARANCE; DRUG DESIGN; DRUG STRUCTURE; ENZYME LOCALIZATION; GLUCOSE BLOOD LEVEL; HUMAN; HUMAN CELL; LIVER MICROSOME; MALE; MOUSE; NONHUMAN; PROTEIN TRANSPORT; RAT; ACTIVE TRANSPORT; ANIMAL; CHEMICAL STRUCTURE; CHEMISTRY; METABOLISM; SPRAGUE DAWLEY RAT; STEREOISOMERISM; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

ACTIVE TRANSPORT, CELL NUCLEUS; ADAPTOR PROTEINS, SIGNAL TRANSDUCING; ANIMALS; BLOOD GLUCOSE; CELL NUCLEUS; CRYSTALLOGRAPHY, X-RAY; CYTOPLASM; GLUCOKINASE; HYPOGLYCEMIC AGENTS; MALE; MICE; MICROSOMES, LIVER; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PROTEIN BINDING; RATS, SPRAGUE-DAWLEY; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES; THIOPHENES;

EID: 84953226350     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b01367     Document Type: Article

References (40)

1. International Diabetes Federation. IDF Diabetes Atlas. http://www.idf.org/ (accessed May 26, 2015).
2. Ettaro, L.; Songer, T. J.; Zhang, P.; Engelgau, M. M. Cost-of-illness studies in diabetes mellitus PharmacoEconomics 2004, 22, 149-164 10.2165/00019053-200422030-00002
3. Seuring, T.; Archangelidi, O.; Suhrcke, M. The economic costs of type 2 diabetes: a global systematic review PharmacoEconomics 2015, 33, 811-831 10.1007/s40273-015-0268-9
4. Verspohl, E. J. Novel pharmacological approaches to the treatment of type 2 diabetes Pharmacol. Rev. 2012, 64, 188-237 10.1124/pr.110.003319
5. Agius, L. Glucokinase and molecular aspects of liver glycogen metabolism Biochem. J. 2008, 414, 1-18 10.1042/BJ20080595
6. Matschinsky, F. M. Glucokinase as glucose sensor and metabolic signal generator in pancreatic β-cells and hepatocytes Diabetes 1990, 39, 647-652 10.2337/diab.39.6.647
7. Matschinsky, F. M.; Glaser, B.; Magnuson, M. A. Pancreatic beta-cell glucokinase: closing the gap between theoretical concepts and experimental realities Diabetes 1998, 47, 307-315 10.2337/diabetes.47.3.307
8. 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
9. Meininger, G. E.; Scott, R.; Alba, M.; Shentu, Y.; Luo, E.; Amin, H.; Davies, M. J.; Kaufman, K. D.; Goldstein, B. J. Effects of MK-0941, a novel glucokinase activator, on glycemic control in insulin-treated patients with type 2 diabetes Diabetes Care 2011, 34, 2560-2566 10.2337/dc11-1200
10. Matschinsky, F. M.; Zelent, B.; Doliba, N.; Li, C.; Vanderkooi, J. M.; Naji, A.; Sarabu, R.; Grimsby, J. Glucokinase activators for diabetes therapy (May 2010 status report) Diabetes Care 2011, 34 (Suppl. 2) S236-S243 10.2337/dc11-s236
11. Rees, M. G.; Gloyn, A. L. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favor? Br. J. Pharmacol. 2013, 168, 335-338 10.1111/j.1476-5381.2012.02201.x
12. Matschinsky, F. M. GKAs for diabetes therapy: why no clinically useful drug after two decades of trying? Trends Pharmacol. Sci. 2013, 34, 90-99 10.1016/j.tips.2012.11.007
13. Filipski, K. J.; Pfefferkorn, J. A. A patent review of glucokinase activators and disruptors of the glucokinase-glucokinase regulatory protein interaction: 2011-2014 Expert Opin. Ther. Pat. 2014, 24, 875-891 10.1517/13543776.2014.918957
14. Anderka, O.; Boyken, J.; Aschenbach, U.; Batzer, A.; Boscheinen, O.; Schmoll, D. Biophysical characterization of the interaction between hepatic glucokinase and its regulatory protein: impact of physiological and pharmacological effectors J. Biol. Chem. 2008, 283, 31333-31340 10.1074/jbc.M805434200
15. Vandercammen, A.; Van Schaftingen, E. The mechanism by which rat liver glucokinase is inhibited by the regulatory protein Eur. J. Biochem. 1990, 191, 483-489 10.1111/j.1432-1033.1990.tb19147.x
16. Lloyd, D. J.; St. Jean, D. J., Jr.; Kurzeja, R. J. M.; Wahl, R. C.; Michelsen, K.; Cupples, R.; Chen, M.; Wu, J.; Sivits, G.; Helmering, J.; Ashton, K. S.; Pennington, L. D.; Fotsch, C. H.; Vazir, M.; Chen, K.; Chmait, S.; Zhang, J.; Liu, L.; Norman, M. H.; Andrews, K. A.; Bartberger, M. D.; Van, G.; Galbreath, E. J.; Vonderfecht, S. L.; Wang, M.; Jordan, S. R.; Veniant, M. M.; Hale, C. Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors Nature 2013, 504, 437-440 10.1038/nature12724
17. Ashton, K. S.; Andrews, K. L.; Bryan, M. C.; Chen, J.; Chen, K.; Chen, M.; Chmait, S.; Croghan, M.; Cupples, R.; Fotsch, C.; Helmering, J.; Jordan, S. R.; Kurzeja, R. J. M.; Michelsen, K.; Pennington, L. D.; Poon, S. F.; Sivits, G.; Van, G.; Vonderfecht, S. L.; Wahl, R. C.; Zhang, J.; Lloyd, D. J.; Hale, C.; St. Jean, D. J., Jr. Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 1. Discovery of a novel tool compound for in vivo proof-of-concept J. Med. Chem. 2014, 57, 309-324 10.1021/jm4016735
18. St. Jean, D. J., Jr.; Ashton, K. S.; Bartberger, M. D.; Chen, J.; Chmait, S.; Cupples, R.; Galbreath, E.; Helmering, J.; Hong, F.-T.; Jordan, S. R.; Liu, L.; Kunz, R. K.; Michelsen, K.; Nishimura, N.; Pennington, L. D.; Poon, S. F.; Reid, D.; Sivits, G.; Stec, M. M.; Tadesse, S.; Tamayo, N.; Van, G.; Yang, K.; Zhang, J.; Norman, M. H.; Fotsch, C.; Lloyd, D. J.; Hale, C. Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 2. Leveraging structure-based drug design to identify analogs with improved pharmacokinetic profiles J. Med. Chem. 2014, 57, 325-338 10.1021/jm4016747
19. Nishimura, N.; Norman, M. H.; Liu, L.; Yang, K. C.; Ashton, K. S.; Bartberger, M. D.; Chmait, S.; Chen, J.; Cupples, R.; Fotsch, C.; Helmering, J.; Jordan, S. R.; Kunz, R. K.; Pennington, L. D.; Poon, S. F.; Siegmund, A.; Sivits, G.; Lloyd, D. J.; Hale, C.; St. Jean, D. J., Jr. Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 3. Structure-activity relationships within the aryl carbinol region of the N-arylsulfonamido-N′-aryl-piperazine series J. Med. Chem. 2014, 57, 3094-3116 10.1021/jm5000497
20. Hong, F.-T.; Norman, M. H.; Ashton, K. S.; Bartberger, M. D.; Chen, J.; Chmait, S.; Cupples, R.; Fotsch, C.; Jordan, S. R.; Lloyd, D. J.; Sivits, G.; Tadesse, S.; Hale, C.; St. Jean, D. J., Jr. Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 4. Exploration of a novel binding pocket J. Med. Chem. 2014, 57, 5949-5964 10.1021/jm5001979
21. Tamayo, N. A.; Norman, M. H.; Bartberger, M. D.; Hong, F.-T.; Bo, Y.; Liu, L.; Nishimura, N.; Yang, K. C.; Tadesse, S.; Fotsch, C.; Chen, J.; Chmait, S.; Cupples, R.; Hale, C.; Jordan, S. R.; Lloyd, D. J.; Sivits, G.; St. Jean, D. J., Jr. Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 5. A novel aryl sulfone series, optimization through conformational analysis J. Med. Chem. 2015, 58, 4462-4482 10.1021/jm5018175
22. For the original design and execution of this GKRP HTS strategy, see the following: Chen, K.; Michelsen, K.; Kurzeja, R. J. M.; Han, J.; Vazir, M.; St. Jean, D. J., Jr.; Hale, C.; Wahl, R. C. Discovery of small-molecule glucokinase regulatory protein modulators that restore glucokinase activity J. Biomol. Screening 2014, 19, 1014-1023 10.1177/1087057114530468
23. cLogP and PSA were calculated with the Daylight Suite, version 4.81, Daylight Chemical Information Systems, Inc.
24. 7.4 were calculated with ACD 2012, Advanced Chemistry Development, Inc. (ACD/Labs).
25. Botta, M.; Corelli, F.; Gasparrini, F.; Messina, F.; Mugnaini, C. Chiral azole derivatives. 4. Enantiomers of bifonazole and related antifungal agents: synthesis, configuration assignment, and biological evaluation J. Org. Chem. 2000, 65, 4736-4739 (see the Supporting Information for details) 10.1021/jo991937p
26. Johansson, M. P.; Olsen, J. Torsional barriers and equilibrium angle of biphenyl: reconciling theory with experiment J. Chem. Theory Comput. 2008, 4, 1460-1471 10.1021/ct800182e
27. For a recent comprehensive review, see the following: Beno, B. R.; Yeung, K.-S.; Bartberger, M. D.; Pennington, L. D.; Meanwell, N. A. A survey of the role of noncovalent sulfur interactions in drug design J. Med. Chem. 2015, 58, 4383-4438 10.1021/jm501853m
28. Yu, G. J.; Yoo, C. L.; Yang, B.; Lodewyk, M. W.; Meng, L.; El-Idreesy, T. T.; Fettinger, J. C.; Tantillo, D. J.; Verkman, A. S.; Kurth, M. J. Potent s-cis-locked bithiazole correctors of δF508 cystic fibrosis transmembrane conductance regulator cellular processing for cystic fibrosis therapy J. Med. Chem. 2008, 51, 6044-6054 10.1021/jm800533c
29. Lin, S.; Wrobleski, S. T.; Hynes, J., Jr.; Pitt, S.; Zhang, R.; Fan, Y.; Doweyko, A. M.; Kish, K. F.; Sack, J. S.; Malley, M. F.; Kiefer, S. E.; Newitt, J. A.; McKinnon, M.; Trzaskos, J.; Barrish, J. C.; Dodd, J. H.; Schieven, G. L.; Leftheris, K. Utilization of a nitrogen-sulfur nonbonding interaction in the design of new 2-aminothiazol-5-ylpyrimidines as p38α MAP kinase inhibitors Bioorg. Med. Chem. Lett. 2010, 20, 5864-5868 10.1016/j.bmcl.2010.07.102
30. All quantum mechanical calculations were performed within the Gaussian 09 program system: Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, revision D.01; Gaussian, Inc.: Wallingford, CT, U.S., 2009.
31. NBO 6.0. Glendening, E. D.; Badenhoop, J. K.; Reed, A. E.; Carpenter, J. E.; Bohmann, J. A.; Morales, C. M.; Landis, C. R.; Weinhold, F. Theoretical Chemistry Institute, University of Wisconsin, Madison, 2013.
32. Weinhold, F.; Landis, C. R. Natural bond orbitals and extensions of localized bonding concepts Chem. Educ. Res. Pract. 2001, 2, 91-104 10.1039/B1RP90011K
33. For a recent review, see the following: Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of fluorine in medicinal chemistry J. Med. Chem. 2015, 58, 8315-8359 10.1021/acs.jmedchem.5b00258
34. St. Jean, D. J., Jr.; Fotsch, C. Mitigating heterocycle metabolism in drug discovery J. Med. Chem. 2012, 55, 6002-6020 10.1021/jm300343m
35. Bartberger, M. D.; Croghan, M. D.; Fotsch, C. H.; Norman, M. H.; Pennington, L. D.; Reichelt, A.; St. Jean, D. J., Jr.; Tegley, C. M. Benzodioxepine and benzodioxine compounds that interact with glucokinase regulatory protein for the treatment of diabetes. WIPO/PCT Pat. Appl. WO 2012138776 A1, 2012.
36. Ashton, K.; Bartberger, M. D.; Bourbeau, M. P.; Croghan, M. D.; Fotsch, C. H.; Hungate, R. W.; Kong, K.; Nishimura, N.; Norman, M. H.; Pennington, L. D.; Reichelt, A.; Siegmund, A. C.; Tadesse, S.; St. Jean, D. J., Jr.; Yang, K. C.; Yao, G. Benzothiophene sulfonamides and other compounds that interact with glucokinase regulatory protein. WIPO/PCT Pat. Appl. WO 2013173382 A1, 2013.
37. For a comprehensive review of the synthetic and stereochemical aspects of tert-butanesulfinylimine chemistry, see the following: Robak, M. T.; Herbage, M. A.; Ellman, J. A. Synthesis and applications of tert-butanesulfinamide Chem. Rev. 2010, 110, 3600-3740 10.1021/cr900382t
38. Assignments of the absolute configuration of 38 and its antipode were determined by comparison of their computed and measured vibrational circular dichroism (VCD) spectra (Stephens, P. J.; Devlin, F. J.; Pan, J.-J. Chirality 2008, 20, 643-663) and optical rotations; see the Supporting Information for details.
39. Akay, S.; Yang, W.; Wang, J.; Lin, L.; Wang, B. Synthesis and evaluation of dual wavelength fluorescent benzo[b]thiophene boronic acid derivatives for sugar sensing Chem. Biol. Drug Des. 2007, 70, 279-289 10.1111/j.1747-0285.2007.00563.x
40. Schlosser, M.; Bobbio, C. Creating structural manifolds from a common precursor: basicity gradient-driven isomerization of halopyridines Eur. J. Org. Chem. 2002, 4174-4180 10.1002/1099-0690(200212)2002:24<4174::AID-EJOC4174>3.0.CO;2-6