title: Design, synthesis, and structure-activity relationships of novel insulin receptor tyrosine kinase activators.
abstract: A novel series of symmetrical ureas of [(7-amino(2-naphthyl))sulfonyl]phenylamines were designed, synthesized, and tested for their ability to increase glucose transport in mouse 3T3-L1 adipocytes, a surrogate readout for activation of the insulin receptor (IR) tyrosine kinase (IRTK). A structure-activity relationship was established that indicated glucose transport activity was dependent on the presence of two acidic functionalities, two sulfonamide linkages, and a central urea or 2-imidazolidinone core. Compound 30 was identified as a potent and selective IRTK activator. At low concentrations, 30 was able to increase the tyrosine phosphorylation of the IR stimulated by submaximal insulin. At higher concentrations, 30 was able to increase tyrosine the phosphorylation levels of the IR in the absence of insulin. When administered intraperitoneally (ip) and orally (po), 30 improved glucose tolerance in hypoinsulinemic, streptozotocin-treated rats. These data provide pharmacological validation that small molecule IRTK activators represent a potential new class of antidiabetic agents.
authors.affiliation: Telik, Inc., 3165 Porter Drive, Palo Alto, California 94304, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Lum
authors.forename: Mingshan
authors.initials: M
authors.lastname: Cheng
authors.forename: Cristina P
authors.initials: CP
authors.lastname: Cristobal
authors.forename: Ira D
authors.initials: ID
authors.lastname: Goldfine
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Evans
authors.forename: James G
authors.initials: JG
authors.lastname: Keck
authors.forename: Robert W
authors.initials: RW
authors.lastname: Macsata
authors.forename: Vara Prasad
authors.initials: VP
authors.lastname: Manchem
authors.forename: Yukiharu
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Sophia J
authors.initials: SJ
authors.lastname: Park
authors.forename: Sandhya S
authors.initials: SS
authors.lastname: Rao
authors.forename: Louise
authors.initials: L
authors.lastname: Robinson
authors.forename: Songyuan
authors.initials: S
authors.lastname: Shi
authors.forename: Wayne R
authors.initials: WR
authors.lastname: Spevak
authors.forename: Steven R
authors.initials: SR
authors.lastname: Schow
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects; D000284:Administration, Oral; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001786:Blood Glucose / Q000032:analysis; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005347:Fibroblasts / Q000187:drug effects; D005951:Glucose Tolerance Test; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000187:drug effects*; D013237:Stereoisomerism; D013311:Streptozocin / Q000008:administration & dosage; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000814:Aniline Compounds; D001786:Blood Glucose; D013449:Sulfonamides; D013311:Streptozocin; D014508:Urea; D011972:Receptor, Insulin