Discovery of a potent, highly selective, and orally efficacious small-molecule activator of the insulin receptor.
A series of 3,6-diaryl-2,5-dihydroxybenzoquinones were synthesized and evaluated for their abilities to selectively activate human insulin receptor tyrosine kinase (IRTK). 2, 5-Dihydroxy-6-(1-methylindol-3-yl)-3-phenyl-1,4-benzoquinone (2h) was identified as a potent, highly selective, and orally active small-molecule insulin receptor activator. It activated IRTK with an EC(50) of 300 nM and did not induce the activation of closely related receptors (IGFIR, EGFR, and PDGFR) at concentrations up to 30 000 nM. Oral administration of the compound to hyperglycemic db/db mice (0.1-10 mg/kg/day) elicited substantial to nearly complete correction of hyperglycemia in a dose-dependent manner. In ob/ob mice, the compound (10 mg/kg) caused significant reduction in hyperinsulinemia. A structurally related compound 2c, inactive in IRTK assay, failed to affect blood glucose level in db/db mice at equivalent exposure levels. Results from additional studies with compound 2h, aimed at evaluating classical quinone-related phenomena, provided sufficient grounds for optimism to allow more extensive toxicologic evaluation.
Liu
K
K
Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA. kun_liu@merck.com
Xu
L
L
Szalkowski
D
D
Li
Z
Z
Ding
V
V
Kwei
G
G
Huskey
S
S
Moller
D E
DE
Heck
J V
JV
Zhang
B B
BB
Jones
A B
AB
D000284:Administration, Oral; D000818:Animals; D016227:Benzoquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D066246:ErbB Receptors / Q000819:agonists; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D051381:Rats; D011972:Receptor, Insulin / Q000819:agonists*; D017479:Receptors, Platelet-Derived Growth Factor / Q000819:agonists; D017451:Receptors, Somatomedin / Q000819:agonists; D013329:Structure-Activity Relationship
C414211:2,5-dihydroxy-6-(1-methylindol-3-yl)-3-phenyl-1,4-benzoquinone; D016227:Benzoquinones; D007004:Hypoglycemic Agents; D007328:Insulin; D017451:Receptors, Somatomedin; D066246:ErbB Receptors; D011972:Receptor, Insulin; D017479:Receptors, Platelet-Derived Growth Factor; D005905:Glyburide