title: Synthesis of 5-chloro-N-aryl-1H-indole-2-carboxamide derivatives as inhibitors of human liver glycogen phosphorylase a.
abstract: A series of 5-chloro-N-aryl-1H-indole-2-carboxamide derivatives were prepared and evaluated as inhibitors of human liver glycogen phosphorylase a (hLGPa). One compound, 5-chloro-N-[4-(1,2-dihydroxyethyl)phenyl]-1H-indole-2-carboxamide (2f), inhibited hLGPa with an IC(50) of 0.90microM. The pyridine analogue of 2f showed inhibitory activity of glucagon-induced glucose output in cultured primary hepatocytes with an IC(50) of 0.62microM and oral hypoglycemic activity in diabetic db/db mice. Crystallographic determination of the complex of 2f with hLGPa showed binding of the inhibitor in a solvent cavity at the dimer interface, with the two hydroxyl groups making favorable electrostatic interactions with hLGPa.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 5-2-3 Toukoudai, Tsukuba, Ibaraki 300-2698, Japan. kenichi.onda@jp.astellas.com
authors.forename: Kenichi
authors.initials: K
authors.lastname: Onda
authors.forename: Takayuki
authors.initials: T
authors.lastname: Suzuki
authors.forename: Ryota
authors.initials: R
authors.lastname: Shiraki
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yonetoku
authors.forename: Kenji
authors.initials: K
authors.lastname: Negoro
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Momose
authors.forename: Naoko
authors.initials: N
authors.lastname: Katayama
authors.forename: Masaya
authors.initials: M
authors.lastname: Orita
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tsukamoto
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018360:Crystallography, X-Ray; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D025001:Glycogen Phosphorylase, Liver Form / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008820:Mice, Obese; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism
chemical_list: C530723:5-chloro-N-(4-(1,2-dihydroxyethyl)phenyl)-1H-indole-2-carboxamide; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007211:Indoles; D025001:Glycogen Phosphorylase, Liver Form