A starting material, 4-bromo-3-fluorobenzaldehyde, was used for active drug substance (API) AMG 369 production. The presence of the regioisomer impurities in the starting material 4-bromo-3-fluorobenzaldehyde presented significant challenges for the API synthetic route development due to the physical-chemical similarities of the impurities. These impurities significantly impact on the purity of the starting-material and final drug substance. Control of these impurities is important due to the potential genotoxicity of these impurities (p-GTI). Analytical development was carried out to develop GC methods with high resolving power and high sensitivity to quantify the regioisomers presented in starting material and therefore to control the purity of the starting material and the final drug substance. In the study, complete resolution of the ten regioisomers by 1D-GC and heart-cutting two-dimensional GC (2D-GC) was achieved. A sensitive GC/micro electron capture detection (μ-ECD) method with high resolving power and sensitivity to fully resolve all the ten regioisomers of 4-bromo-3-fluorobenzaldehyde was obtained by using a CHIRALDEX GC column (1D- GC). To facilitate the systematic GC method development, heart-cutting two-dimensional gas chromatography (2D-GC) using a Deans switch was exploited for the separation of the ten regioisomers. The resulting heart-cutting 2D-GC method successfully separated all the ten regioisomers with better sensitivity and resolution. Regioisomer impurities in the starting material were identified and quantified by these GC methods. The sensitivity for the methods is in the range of 0.004ng to 0.02ng for the regioisomers. Linearity for the methods is: R(2)=0.999 to 1.000. The methods were suitable for control of the regioisomer impurities, p-GTIs, in the starting material and final drug substance.

2012-02-01·Bioorganic & Medicinal Chemistry Letters4区 · 医学

Isoform-selective thiazolo[5,4-b]pyridine S1P1 agonists possessing acyclic amino carboxylate head-groups

4区 · 医学

Article

作者: Fiorino, Mike ; Itano, Andrea ; Xu, Han ; Middleton, Scot ; Gore, Anu ; Pickrell, Alexander J. ; Harrington, Paul E. ; Frohn, Mike ; Lanman, Brian A. ; Neira, Susana ; Wong, Min ; Tasker, Andrew S. ; Sham, Kelvin K. C. ; Morrison, Henry ; McElvain, Michele ; Cee, Victor J. ; Reed, Anthony B. ; Xu, Yang

Replacement of the azetidine carboxylate of an S1P(1) agonist development candidate, AMG 369, with a range of acyclic head-groups led to the identification of a novel, S1P(3)-sparing S1P(1) agonist, (-)-2-amino-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-2-methylbutanoic acid (8c), which possessed good in vivo efficacy and pharmacokinetic properties. A 0.3mg/kg oral dose of 8c produced a statistically significant reduction in blood lymphocyte counts 24h post-dosing in female Lewis rats.

2011-02-10·ACS Medicinal Chemistry Letters3区 · 医学

Discovery of AMG 369, a Thiazolo[5,4-b]pyridine Agonist of S1P₁ and S1P₅

3区 · 医学

Article

作者: Rivenzon-Segal, Dalia ; Muller, Kristine ; Schrag, Michael ; Lee, Matt R. ; Xu, Han ; Frohn, Mike ; Siu, Jerry ; Vargas, Hugo M. ; Bürli, Roland W. ; Wong, Min ; Xu, Yang ; Arnett, Heather ; Cee, Victor J. ; Pickrell, Alex ; Gore, Anu ; Buys, Janet ; Lanman, Brian A. ; Horner, Michelle ; Zhang, Xuxia ; McElvain, Michele ; Golden, Jennifer ; Middleton, Scot ; Itano, Andrea ; Fiorino, Mike ; Neira, Susana

The optimization of a series of thiazolopyridine S1P1 agonists with limited activity at the S1P3 receptor is reported. These efforts resulted in the discovery of 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo-[5,4-b]pyridin-2-yl)benzyl)azetidine-3-carboxylic acid (5d, AMG 369), a potent dual S1P1/S1P5 agonist with limited activity at S1P3 and no activity at S1P2/S1P4. Dosed orally at 0.1 mg/kg, 5d is shown to reduce blood lymphocyte counts 24 h postdose and delay the onset and reduce the severity of experimental autoimmune encephalomyelitis in rat.

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