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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.

Nishimura N, Norman MH, Liu L, Yang KC, Ashton KS, Bartberger MD, Chmait S, Chen J, Cupples R, Fotsch C, Helmering J, Jordan SR, Kunz RK, Pennington LD, Poon SF, Siegmund A, Sivits G, Lloyd DJ, Hale C, St Jean DJ
J Med Chem 57 3094-116 (2014)
Related entries: 4ohk, 4oho, 4ohp

Cited: 16 times
EuropePMC logo PMID: 24611879

Abstract

We have recently reported a novel approach to increase cytosolic glucokinase (GK) levels through the binding of a small molecule to its endogenous inhibitor, glucokinase regulatory protein (GKRP). These initial investigations culminated in the identification of 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1, AMG-3969), a compound that effectively enhanced GK translocation and reduced blood glucose levels in diabetic animals. Herein we report the results of our expanded SAR investigations that focused on modifications to the aryl carbinol group of this series. Guided by the X-ray cocrystal structure of compound 1 bound to hGKRP, we identified several potent GK-GKRP disruptors bearing a diverse set of functionalities in the aryl carbinol region. Among them, sulfoximine and pyridinyl derivatives 24 and 29 possessed excellent potency as well as favorable PK properties. When dosed orally in db/db mice, both compounds significantly lowered fed blood glucose levels (up to 58%).

Reviews citing this publication (5)

  1. Glucokinase regulatory protein: complexity at the crossroads of triglyceride and glucose metabolism. Raimondo A, Rees MG, Gloyn AL. Curr Opin Lipidol 26 88-95 (2015)
  2. Molecular targeting of the GK-GKRP pathway in diabetes. Hale C, Lloyd DJ, Pellacani A, Véniant MM. Expert Opin Ther Targets 19 129-139 (2015)
  3. Piperazine skeleton in the structural modification of natural products: a review. Zhang RH, Guo HY, Deng H, Li J, Quan ZS. J Enzyme Inhib Med Chem 36 1165-1197 (2021)
  4. Determination of the Absolute Configurations of Chiral Drugs Using Chiroptical Spectroscopy. Polavarapu PL. Molecules 21 E1056 (2016)
  5. Conformational control in structure-based drug design. Zheng Y, Tice CM, Singh SB. Bioorg Med Chem Lett 27 2825-2837 (2017)

Articles citing this publication (11)

  1. Novel Pieces for the Emerging Picture of Sulfoximines in Drug Discovery: Synthesis and Evaluation of Sulfoximine Analogues of Marketed Drugs and Advanced Clinical Candidates. Sirvent JA, Lücking U. ChemMedChem 12 487-501 (2017)
  2. Harnessing Sulfinyl Nitrenes: A Unified One-Pot Synthesis of Sulfoximines and Sulfonimidamides. Davies TQ, Tilby MJ, Ren J, Parker NA, Skolc D, Hall A, Duarte F, Willis MC. J Am Chem Soc 142 15445-15453 (2020)
  3. Modular Sulfondiimine Synthesis Using a Stable Sulfinylamine Reagent. Zhang ZX, Davies TQ, Willis MC. J Am Chem Soc 141 13022-13027 (2019)
  4. Bianthryl-based organocatalysts for the asymmetric Henry reaction of fluoroketones. Otevrel J, Svestka D, Bobal P. Org Biomol Chem 17 5244-5248 (2019)
  5. Discovery of orally active hepatoselective glucokinase activators for treatment of Type II Diabetes Mellitus. Xu J, Lin S, Myers RW, Trujillo ME, Pachanski MJ, Malkani S, Chen HS, Chen Z, Campbell B, Eiermann GJ, Elowe N, Farrer BT, Feng W, Fu Q, Kats-Kagan R, Kavana M, McMasters DR, Mitra K, Tong X, Xu L, Zhang F, Zhang R, Addona GH, Berger JP, Zhang B, Parmee ER. Bioorg Med Chem Lett 27 2063-2068 (2017)
  6. Antidiabetic Disruptors of the Glucokinase-Glucokinase Regulatory Protein Complex Reorganize a Coulombic Interface. Martinez JA, Xiao Q, Zakarian A, Miller BG. Biochemistry 56 3150-3157 (2017)
  7. NH-sulfoximine: A novel pharmacological inhibitor of the mitochondrial F1 Fo -ATPase, which suppresses viability of cancerous cells. Strobbe D, Pecorari R, Conte O, Minutolo A, Hendriks CMM, Wiezorek S, Faccenda D, Abeti R, Montesano C, Bolm C, Campanella M. Br J Pharmacol 178 298-311 (2021)
  8. Synthesis, Physicochemical Properties, and Biological Activities of 4-(S-Methyl-N-(2,2,2-Trifluoroacetyl)Sulfilimidoyl) Anthranilic Diamide. Lim HJ, Lee WH, Park SJ. Molecules 24 E3451 (2019)
  9. Accessing Perfluoroaryl Sulfonimidamides and Sulfoximines via Photogenerated Perfluoroaryl Nitrenes: Synthesis and Application as a Chiral Auxiliary. Proietti G, Kuzmin J, Temerdashev AZ, Dinér P. J Org Chem 86 17119-17128 (2021)
  10. N-Cyano sulfilimine functional group as a nonclassical amide bond bioisostere in the design of a potent analogue to anthranilic diamide insecticide. Kang OY, Kim E, Lee WH, Ryu DH, Lim HJ, Park SJ. RSC Adv 13 2004-2009 (2023)
  11. Synthesis of aryl cyclopropyl sulfides through copper-promoted S-cyclopropylation of thiophenols using cyclopropylboronic acid. Benoit E, Fnaiche A, Gagnon A. Beilstein J Org Chem 15 1162-1171 (2019)


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