The Discovery of GSK2251052: A First-in-Class Boron ... - Anacor

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40 Improved Medchem Process was used to Produce Phase I Clinical Trial Material OH OH BnO Br O OH OBn Tf 2 O, Pyridine O OTf OBn CHO t-BuONa, DMSO rt, O/N quantitative CHO DCM, rt, 3 h 64-88% CHO O O BB O O PdCl 2 (dppf), KOAc THF or dioxane 50-75% BnO O OH B O NaOH(aq.), CH 3 NO 2 THF, 0 o Ctort,O/N 55-60% BnO O O B O CHO NO 2 50% yield 1)Pd(OH) 2 ,NH 3 in MeOH 2) HCl in MeOH HO O AN3213 (racemic) OH B O NH 2 .HCl HO 1) NH 3 in MeOH 2) R-(-)-mandelic acid 3) aq. HCl 47% yield O GSK2251052 OH B O NH 2 .HCl
41 Process Research at GSK Identified a Stereospecific Route to GSK2251052 Conde, JJ. WO 2011127143
Page 1 and 2: The Discovery of GSK2251052: A Firs
Page 3 and 4: Bacterial Infections in Pre-antibio
Page 5 and 6: 5 Antibiotic Resistance is Increasi
Page 7 and 8: Genomic Revolution did not Improve
Page 9 and 10: Boron Chemistry: A New Approach to
Page 11 and 12: 11 General Facts on Boron Boron is
Page 13 and 14: History and Overview of Boronic Aci
Page 15 and 16: 15 Anacor’s Approach to Drug-like
Page 17 and 18: 17 Re-discovery of the Benzoxaborol
Page 19 and 20: 19 AN2690 (Tavaborole) was Shown to
Page 21 and 22: 21 Leucyl-tRNA synthetase (LeuRS) E
Page 23 and 24: X-ray Structure Revealed A tRNA Leu
Page 25 and 26: AN2690 Traps tRNA Leu in Editing Si
Page 27 and 28: 27 AN2690 had Poor In vitro Activit
Page 29 and 30: 29 3-Aminomethyl Substitution was A
Page 31 and 32: 31 Improving Spectrum of Activity f
Page 33 and 34: 33 Key Interactions Identified in X
Page 35 and 36: 35 GSK2251052 In Vitro Activity: En
Page 37 and 38: 37 GSK2251052: Pre-Clinical Mechani
Page 39: 39 Initial Medchem Synthesis Relied
Page 43 and 44: 43 GSK2251052 Phase 1 Results Showe
Page 45 and 46: 45 Efficacy of Recreated Human IV E
Page 47 and 48: 47 Talk Summary Multi-drug resista

The Discovery of GSK2251052: A First-in-Class Boron ... - Anacor

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