Amino acid anthranilamide derivatives as a new class of glycogen phosphorylase inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 14, 2008, Pages 4068-4071

  Evans, Karen A ^a   Li, Yue H ^a   Coppo, Frank T ^a   Graybill, Todd L ^a   Cichy Knight, Maria ^a   Patel, Mehul ^a   Gale, Jennifer ^a   Li, Hu ^a   Thrall, Sara H ^a   Tew, David ^a   Tavares, Francis ^a   Thomson, Stephen A ^a   Weiel, James E ^a   Boucheron, Joyce A ^a   Clancy, Daphne C ^a   Epperly, Andrea H ^a   Golden, Pamela L ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

Glycogen phosphorylase inhibitors; Human liver glycogen phosphorylase; Solid phase synthesis

Indexed keywords

AMINO ACID ANTHRANILAMIDE DERIVATIVE; AMINO ACID DERIVATIVE; ANILINE DERIVATIVE; ENZYME INHIBITOR; GLUCOSE; GLYCOGEN PHOSPHORYLASE; GLYCOGEN PHOSPHORYLASE INHIBITOR; RESIN; WANG RESIN;

ARTICLE; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HIGH THROUGHPUT SCREENING; HUMAN; IC 50; IN VITRO STUDY; LIVER; SOLID PHASE SYNTHESIS; STRUCTURE ACTIVITY RELATION;

AMINO ACIDS; ANIMALS; ANTHRANILIC ACIDS; CHEMISTRY, PHARMACEUTICAL; DRUG DESIGN; GLYCOGEN PHOSPHORYLASE, LIVER FORM; HUMANS; INHIBITORY CONCENTRATION 50; LIVER; MICROSOMES, LIVER; MODELS, CHEMICAL; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; UREA;

EID: 47149095020     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.05.102     Document Type: Article

References (15)

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7. 50 values given in Tables 1-4 are average values of at least 2 replicates where standard deviations are noted, and were measured in the presence of glucose. See Ref. 7 for additional details.
8. The Wang resin was obtained from Polymer Laboratories, 1.7 mmol/g (PL-Wang, Product # 1463, 150-300 μm).
9. Sieber P. Tetrahedron Lett. 28 (1987) 6147
10. Commercially available resins preloaded with L-amino acids were obtained from Polymer Labs (www.polymerlabs.com), typically 0.86 mmol/g, >99% optical purity.
11. For further experimental details, see Evans, K.A.; Cichy-Knight, M.; Coppo, F.T.; Dwornik, K.A.; Gale, J.P.; Garrido, D.M.; Li, Y.H.; Patel, M.; Tavares, F.X.; Thomson, S.A.; Dickerson, S.H.; Peat, A.J.; Sparks, S.M.; Banker, P.; Cooper, J.P. WO 2006/052722 A1.
12. 2O, 0.1% TFA) with UV detection at 254 nm was typically used.
13. 2O containing 0.02% TFA (3.6 min gradient) and monitored by a UV detector operating at 214 nm and by a SEDEX 75 evaporative light scattering detector (ELSD) operating at 42 °C. LCMS M+H signals were consistent with expected molecular weight for all reported products.
14. 50 values given in Tables 1-4 are average values of at least 2 replicates where standard deviations are noted.
15. + = 494.4.