title: Discovery of a series of nonpeptide small molecules that inhibit the binding of insulin-like growth factor (IGF) to IGF-binding proteins.
abstract: Insulin-like growth factors (IGF-I and II) play an important role in metabolic and mitogenic activities through stimulation of the IGF-I receptor on the cell surface. Although the concentration of IGF in blood and cerebrospinal fluid is quite high (>100 nM), this large pool of IGF is biologically inactive because of its association with six distinct binding proteins, which form high-affinity complexes with IGF. Thus, inhibitors of IGF-binding proteins (IGFBPs), especially IGFBP-3, could potentially alter the distribution between the "free" and "bound" forms of IGF and thereby elevate biologically active IGF-I to exert a beneficial effect on those patients with diseases that respond to the application of exogenous IGF-I. Whereas IGF-I peptide variants, which bind to IGFBPs but not the IGF-I receptor, have been shown to be potent IGF/IGFBP inhibitors, small molecule nonpeptide IGF/IGFBP inhibitors have the potential advantages of oral bioavailability and flexible dosing regimen. Here we report the discovery of several isoquinoline analogues, exemplified by 1 and 2, which bind IGFBP-3 as well as other IGFBPs at low nanomolar concentrations. More importantly, both compounds were shown to be able to release biologically active IGF-I from the IGF-I/IGFBP-3 complex. These results point to the feasibility of developing orally active therapeutics to treat IGF-responsive diseases by optimization of the lead molecules 1 and 2.
authors.affiliation: Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, California 92121, USA. cchen@neurocrine.com
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.forename: Y F
authors.initials: YF
authors.lastname: Zhu
authors.forename: X J
authors.initials: XJ
authors.lastname: Liu
authors.forename: Z X
authors.initials: ZX
authors.lastname: Lu
authors.forename: Q
authors.initials: Q
authors.lastname: Xie
authors.forename: N
authors.initials: N
authors.lastname: Ling
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C439967:1-(3,4-dihydroxybenzoyl)-3-hydroxy-6,7-dihydroxyisoquinoline; C439968:1-(3,4-dihydroxybenzoyl)-3-hydroxycarbonyl-6,7-dihydroxyisoquinoline; D007546:Isoquinolines; D017527:Receptor, IGF Type 2; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1