RO-28-1675
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This article, RO-28-1675, was written by RelentlessRecusant. Please do not edit this fiction without the writer's permission. |
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RO-28-1675, IUPAC name (R)-3-cyclopentyl-2-(4-(methylsulfonyl)phenyl)-N-(thiazol-2-yl)propanamide, is a chiral small-molecule specific allosteric activator of glucokinase (hexokinase IV). It was originally synthesized and characterized by Grimsby et. al in 2003 by a collaboration between Hoffmann-La Roche Inc., the Department of Biochemistry and Diabetes Center at the University of Pennsylvania School of Medicine, and the Department of Molecular Physiology and Biophysics at Vanderbilt University.[1]
It was originally discovered as a hit compound on a high-throughput screen of 120,000 structurally-diverse synthetic compounds and the hit compound underwent structure-activity relationship (SAR) studies to lead to a chemically optimized lead compound, RO-28-0450. Enantiomeric separation led to the resolution of the R enantiomer, RO-28-1675 as the biologically active compound in the achiral mixture.[1]
RO-28-1675 is a direct enzymatic activator of the human glucokinase enzyme, increasing enzymatic kinetics (Vmax) without interfering with affinity for its substrates. RO-28-1675 is a biologically-active compound, halving the amount of glucose necessary to induce glucose-stimulated insulin secretion (GSIS) in purified rat islets, normalizing blood glucose in diet-induced obese (DIO) diabetes mouse models across several mouse backgrounds to 50mg/mL, and increasing blood insulin concentrations five-fold[1], demonstrating the clinical utility of RO-28-1675 as an anti-diabetic drug and as an in vitro research tool.
[edit] References
- ↑ 1.0 1.1 1.2 Grimsby et. al (2003). Allosteric Activators of Glucokinase: Potential Role in Diabetes Therapy. Science (301): 370-373.
| Chemical Biology: Small-Molecule Control of Biological Systems (RelentlessRecusant) | ||
|---|---|---|
| | ||
| Receptor Tyrosine Kinases | A-83-01 (TGFβ/Activin) · BPIQ-II (EGFR) · Dorsomorphin/LDN-193189 (TGFβ/BMP) · SU5402 (FGFR) | |
| Signaling Kinases | A-769662 (AMPK) · BMS-354825 (BCR-ABL, Src)· BIO-Acetoxime (GSK3) · CHIR99021 (GSK3) · GO 6976 (PKC) · IMD-0354 (IκBa) · PD184352 (MAPK) · SB203580 (MAPK) · Y-27632 (ROCK) | |
| G Protein-Coupled Receptor | (+)-WIN-55212 (CB1/CB2) · ±-Sulpride (D2) · A 841720 (mGluR1) · BP-554 (5-HT1A) · Hh-Ag1.5 (Smo) · Cyclopamine/KAAD-Cyclopamine (Smo) · SANT1 (Smo) · SB-277011 (D3) | |
| Ion Channels | BAY K8644 (Cav1.2) · Bicuculline (GABAAR) · Cymarin (Na+/H+) · G-strophanthin (Na+/H+) · L-AP4 (Na+/H+) · Oxcarbazepine (Na+) · Resiniferatoxin (TRPV1) · Sarmentogenin (Na+/H+) · Theanine (AMPAR, NMDAR) | |
| Transporters | O-1783 (DAT) · WF-23 (DAT, SERT) | |
| Nuclear Receptor | All-trans retinoic acid (RAR/RXR) · GW501516 (PPARδ) · RU-486 (Nr3c1, Nr3c3) | |
| Protein Phosphatases | Endothall (PP2A) | |
| Polypharmacological | Phosphoserine (mGluR4) · PK115-584 (Tcf4/β-catenin, PKC) · Pluripotin · Reversine | |
| Other | 2C-E (DAT) · 4-methoxyphenyl-HTI-286 (α/β-tubulin) · Compound E/DAPT (presenilin-1) · D-cysteine · D-phenylalanine · Flurbiprofen (COX) · JZL184 (MAGL) · QS11 (RAFGAP1) · RO-28-1675 (glucokinase) · Robotnikinin (Shh) · Selegiline (MAOB) | |
| Uncharacterized | Neuropathiazol | |
| Libraries | Kinase Inhibitor Library | |
| Publications | ||
| Small molecule-mediated manipulation of the adult human induces selective and reversible control of physiological and psychological phenotype (Rubin et. al, 2590. Nature Medicine) | ||
| Source · Edit | ||
