Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 3. Structure-activity relationships within the aryl carbinol region of the N-arylsulfonamido-N′-arylpiperazine series

Journal of Medicinal Chemistry

Volumn 57, Issue 7, 2014, Pages 3094-3116

  Nishimura, Nobuko ^a   Norman, Mark H ^a   Liu, Longbin ^a   Yang, Kevin C ^a   Ashton, Kate S ^a   Bartberger, Michael D ^a   Chmait, Samer ^a   Chen, Jie ^a   Cupples, Rod ^a   Fotsch, Christopher ^a   Helmering, Joan ^a   Jordan, Steven R ^a   Kunz, Roxanne K ^a   Pennington, Lewis D ^a   Poon, Steve F ^a   Siegmund, Aaron ^a   Sivits, Glenn ^a   Lloyd, David J ^a   Hale, Clarence ^a   St Jean, David J ^a  

^a AMGEN INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 [4 [ 4 [(6 AMINO 3 PYRIDINYL)SULFONYL] 2 (1 PROPYN 1 YL) 1 PIPERAZINYL]PHENYL]ETHANONE; 2 [2 [4 [(6 AMINO 3 PYRIDINYL)SULFONYL] 2 (1 PROPYN 1 YL) 1 PIPERAZINYL] 1,3 THIAZOL 5 YL] 1,1,1 TRIFLUORO 2 PROPANOL; 2 [4 [4 [(6 AMINO 3 PYRIDINYL)SLFONYL] 2 (1 PROPYN 1 YL) 1 PIPERAZINYL]PHENYL] 1,1,1,3,3,3 HEXAFLUORO 2 PROPANOL; 2 [5 [ 4 [(6 AMINO 3 PYRIDINYL)SULFONYL] 2 (1 PROPYN 1 YL) 1 PIPERAZINYL] 2 PYRIDINYL] 1,1,1 TRIFLUORO 2 PROPANOL; 2 [6 [ 4 [(6 AMINO 3 PYRIDINYL)SULFONYL] 2 (1 PROPYN 1 YL) 1 PIPERAZINYL] 3 PYRIDINYL] 1,1,1,3,3,3 HEXAFLUORO 2 PROPANOL; 2 [6 [ 4 [(6 AMINO 3 PYRIDINYL)SULFONYL] 2 (1 PROPYN 1 YL) 1 PIPERAZINYL] 3 PYRIDINYL] 1,1,1,3,3,3 TRIFLUORO 2 PROPANOL; 4 [ 4 [(6 AMINO 3 PYRIDINYL)SULFONYL] 2 (1 PROPYN 1 YL) 1 PIPERAZINYL] N (1 METHYLETHYL)BENZENESULFONAMIDE; 4 [ 4 [(6 AMINO 3 PYRIDINYL)SULFONYL] 2 (1 PROPYN 1 YL) 1 PIPERAZINYL] N (CYCLOPROPYLMETHYL)BENZENESULFONAMIDE; 4 [ 4 [(6 AMINO 3 PYRIDINYL)SULFONYL] 2 (1 PROPYN 1 YL) 1 PIPERAZINYL] N CYCLOPROPYLBENZENESULFONAMIDE; 4 [ 4 [(6 AMINO 3 PYRIDINYL)SULFONYL] 2 (1 PROPYN 1 YL) 1 PIPERAZINYL] N METHYLBENZAMIDE; 4 [ 4 [(6 AMINO 3 PYRIDINYL)SULFONYL] 2 (1 PROPYN 1 YL) 1 PIPERAZINYL] N METHYLBENZENESULFONAMIDE; 4 [ 4 [(6 AMINO 3 PYRIDINYL)SULFONYL] 2 (1 PROPYN 1 YL) 1 PIPERAZINYL] N PHENYLBENZENESULFONAMIDE; 4 [ 4 [(6 AMINO 3 PYRIDINYL)SULFONYL] 2 (1 PROPYN 1 YL) 1 PIPERAZINYL]BENZENESULFONAMIDE; 5 [[ 3 (1 PROPYN 1 YL) 4 [4 (2,2,2 TRIFLUORO 1 METHYLETHYL)PHENYL] 1 PIPERAZINYL]SULFONYL] 2 PYRIDINAMINE; 5 [[ 3 (1 PROPYN 1 YL) 4 [4 [S (TRIFLUOROMETHYL) SULFONIMIDOYL]PHENYL] 1 PIPERAZINYL]SULFONYL] 2 PYRIDINAMINE; 5 [[ 4 PHENYL 3 (1 PROPYN 1 YL) 1 PIPERAZINYL]SULFONYL] 2 PYRIDINAMINE; 5 [[ 4 [4 (S CYCLOPROPYLSULFONIMIDOYL)PHENYL] 3 (1 PROPYN 1 YL) 1 PIPERAZINYL]SULFONYL] 2 PYRIDINAMINE; 5 [[ 4 [4 (S METHYLSULFONIMIDOYL)PHENYL] 3 (1 PROPYN 1 YL) 1 PIPERAZINYL]SULFONYL] 2 PYRIDINAMINE; 5 [[ 4 [4 [N METHYL S (TRIFLUOROMETHYL)SULFONIMIDOYL] PHENYL] 3 (1 PROPYN 1 YL) 1 PIPERAZINYL]SULFONYL] 2 PYRIDINAMINE; 5 [[ 4 [4(METHYLSULFONYL)PHENYL] 3 (1 PROPYN 1 YL) 1 PIPERAZINYL]SULFONYL] 2 PYRIDINAMINE; 5 [[4 [4 (METHYLSULFINYL)PHENYL] 3 (1 PROPYN 1 YL) 1 PIPERAZINYL]SULFONYL] 2 PYRIDINAMINE; 6 [ 4 [(6 AMINO 3 PYRIDINYL)SULFONYL] 2 (1 PROPYN 1 YL) 1 PIPERAZINYL] N METHYL 3 PYRIDINESULFONAMIDE; GLUCOKINASE; GLUCOKINASE REGULATORY PROTEIN; GLUCOSE; METHANOL; N ARYLSULFONAMIDO N' ARYLPIPERAZINE; PIPERAZINE DERIVATIVE; REGULATOR PROTEIN; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANIMAL CELL; ARTICLE; BINDING ASSAY; CRYSTAL STRUCTURE; GLUCOSE BLOOD LEVEL; HYDROGEN BOND; LIVER CELL; LIVER MICROSOME; MOLECULAR SIZE; MOUSE; NONHUMAN; PROTEIN PROTEIN INTERACTION; STRUCTURE ACTIVITY RELATION;

ANIMALS; BIOLOGICAL AVAILABILITY; BLOOD GLUCOSE; CARRIER PROTEINS; CRYSTALLOGRAPHY, X-RAY; DIABETES MELLITUS; DISEASE MODELS, ANIMAL; GLUCOKINASE; HEPATOCYTES; HYPOGLYCEMIC AGENTS; MICE; MICROSOMES, LIVER; MODELS, MOLECULAR; PIPERAZINES; RATS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES;

EID: 84898408293     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm5000497     Document Type: Article

References (24)

1. International Diabetes Federation. IDF Diabetes Atlas. http://www.idf.org/ (accessed Aug 13, 2013).
2. Verspohl, E. J. Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes Pharmacol. Rev. 2012, 64, 188-237
3. 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, S236-S243
4. Matschinsky, F. M. GKAs for Diabetes Therapy: Why No Clinically Useful Drug after Two Decades of Trying? Trends Pharmacol. Sci. 2013, 34, 90-99
5. Pfefferkorn, J. A.; Guzman-Perez, A.; Litchfield, J.; Aiello, R.; Treadway, J. L.; Pettersen, J.; Minich, M. L.; Filipski, K. J.; Jones, C. S.; Tu, M.; Aspnes, G.; Risley, H.; Bian, J.; Stevens, B. D.; Bourassa, P.; D'Aquila, T.; Baker, L.; Barucci, N.; Robertson, A. S.; Bourbonais, F.; Derksen, D. R.; MacDougall, M.; Cabrera, O.; Chen, J.; Lapworth, A. L.; Landro, J. A.; Zavadoski, W. J.; Atkinson, K.; Haddish-Berhane, N.; Tan, B.; Yao, L.; Kosa, R. E.; Varma, M. V.; Feng, B.; Duignan, D. B.; El-Kattan, A.; Murdande, S.; Liu, S.; Ammirati, M.; Knafels, J.; DaSilva-Jardine, P.; Sweet, L.; Liras, S.; Rolph, T. P. Discovery of (S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1 H -imidazol-1-yl)propanamido)nicotinic Acid as a Hepatoselective Glucokinase Activator Clinical Candidate for Treating Type 2 Diabetes Mellitus J. Med. Chem. 2012, 55, 1318-1333
6. Baltrusch, S.; Tiedge, M. Glucokinase Regulatory Network in Pancreatic β-Cells and Liver Diabetes 2006, 55, S55-S64
7. 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.; Vazir, M.; Chen, K.; Chmait, S.; Zhang, J.; Liu, L.; Norman, M. H.; Andrews, K. L.; Bartberger, M. D.; Van, G.; Galbreath, E. J.; Vonderfecht, S. L.; Wang, M.; Jordan, S. R.; Véniant, M. M.; Hale, C. Antidiabetic Effects of Glucokinase Regulatory Protein Small Molecule Disruptors Nature 2013, 504, 437-440
8. 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
9. 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. C.; 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 Analogues with Improved Pharmacokinetic Profiles J. Med. Chem. 2014, 57, 325-338
10. Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. A New Class of Easily Activated Palladium Precatalysts for Facile C-N Cross-Coupling Reactions and the Low Temperature Oxidative Addition of Aryl Chlorides J. Am. Chem. Soc. 2008, 130, 6686-6687
11. Maiti, D.; Fors, B. P.; Henderson, J. L.; Nakamura, Y.; Buchwald, S. L. Palladium-Catalyzed Coupling of Functionalized Primary and Secondary Amines with Aryl and Heteroaryl Halides: Two Ligands Suffice in Most Cases Chem. Sci. 2011, 2, 57-68
12. Surry, D. S.; Buchwald, S. L. Dialkylbiaryl Phosphines in Pd-Catalyzed Amination: A User's Guide Chem. Sci. 2011, 2, 27-50
13. Olofson, R. A.; Martz, J. T.; Senet, J. P.; Piteau, M.; Malfroot, T. A New Reagent for the Selective, High-Yield N-Dealkylation of Tertiary Amines: Improved Syntheses of Naltrexone and Nalbuphine J. Org. Chem. 1984, 49, 2081-2082
14. The absolute configurations of the sulfoximine stereocenters in compounds 23 and 24 and the carbinol stereocenters in 29 and 30 were determined by separation of the corresponding racemic aryl bromide starting materials (89 and 90) and stereochemical assignment of each enantiomer by VCD (see the following: Stephens, P. J.; Devlin, F. J.; Pan, J.-J the Determination of the Absolute Configurations of Chiral Molecules Using Vibrational Circular Dichroism (VCD) Spectroscopy. Chirality 2008, 20, 643-663).
15. See Supporting Information for further details. Each enantiomerically pure aryl bromide was then taken through the same synthetic sequence as described in Scheme 1 to provide the final products the retention times of the products prepared in this manner were compared with the retention times of the diastereomers obtained from the original chiral separations to make the absolute stereochemical assignments for compounds 23, 24, 29, and 30.
16. Johnson, C. R.; Haake, M.; Schroeck, C. W. Chemistry of Sulfoxides and Related Compounds. XXVI. Preparation and Synthetic Applications of (Dimethylamino)phenyloxosulfonium Methylide J. Am. Chem. Soc. 1970, 92, 6594-6598
17. Singh, R. P.; Cao, G.; Kirchmeier, R. L.; Shreeve, J. M. Cesium Fluoride Catalyzed Trifluoromethylation of Esters, Aldehydes, and Ketones with (Trifluoromethyl)trimethylsilane J. Org. Chem. 1999, 64, 2873-2876
18. Mizuta, S.; Shibata, N.; Akiti, S.; Fujimoto, H.; Nakamura, S.; Toru, T. Cinchona Alkaloids/TMAF Combination-Catalyzed Nucleophilic Enantioselective Trifluoromethylation of Aryl Ketones Org. Lett. 2007, 9, 3707-3710
19. Hogan, P. J.; Cox, B. G. Aqueous Process Chemistry: The Preparation of Aryl Sulfonyl Chlorides Org. Process Res. Dev. 2009, 13, 875-879
20. Reggelin, M.; Zur, C. Sulfoximines: Structures, Properties, and Synthetic Applications Synthesis 2000, 1-64
21. Meanwell, N. A. Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design J. Med. Chem. 2011, 54, 2529-2591
22. Lu, D.; Vince, R. Discovery of Potent HIV-1 Protease Inhibitors Incorporating Sulfoximine Functionality Bioorg. Med. Chem. Lett. 2007, 17, 5614-5619
23. Daylight Chemical Information Systems, Inc. http://www.daylight.com.
24. Cho, S. J.; Sun, X.; Harte, W. J. Comput.-Aided Mol. Des. 2006, 20, 249-261