Design, synthesis, and structure-activity relationships of novel insulin receptor tyrosine kinase activators.
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.
Lum
Robert T
RT
Telik, Inc., 3165 Porter Drive, Palo Alto, California 94304, USA.
Cheng
Mingshan
M
Cristobal
Cristina P
CP
Goldfine
Ira D
ID
Evans
Joseph L
JL
Keck
James G
JG
Macsata
Robert W
RW
Manchem
Vara Prasad
VP
Matsumoto
Yukiharu
Y
Park
Sophia J
SJ
Rao
Sandhya S
SS
Robinson
Louise
L
Shi
Songyuan
S
Spevak
Wayne R
WR
Schow
Steven R
SR
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*
D000814:Aniline Compounds; D001786:Blood Glucose; D013449:Sulfonamides; D013311:Streptozocin; D014508:Urea; D011972:Receptor, Insulin