Kinase-independent phosphoramidate S1P 1 receptor agonist benzyl ether derivatives

Abstract

Previously published S1P receptor modulator benzyl ether derivatives have shown potential as being viable therapeutics for the treatment of neurodegenerative diseases, however, two of the most S1P-selective compounds are reported as being poorly phosphorylated by kinases in vivo. Phosphoramidates of BED compounds (2a, 2b) were synthesised with the aim of producing kinase-independent S1P receptor modulators. Carboxypeptidase, human serum and cell lysate processing experiments were conducted. ProTide BED analogues were found to have an acceptable level of stability in acidic and basic conditions and in vitro metabolic processing experiments showed that they are processed to the desired pharmacologically active monophosphate. The research describes the development of an entirely novel family of therapeutic agents.

Targeting GNE Myopathy: A Dual Prodrug Approach for the Delivery of N-Acetylmannosamine 6-Phosphate

“…LC-MS analysis of other phosphoramidates, whose purification was attempted after hydrogenation, led to similar results that indicated the formation of compound IV-like structures (m/z values were in agreement with the amino acid ester present in the parent compound). In addition, 31 A plausible mechanism for the formation of by-product IV is proposed in Figure 3.…”

“…Lec3 CHO cell and GNEM patient-derived myoblasts, respectively, at 1 mM. Light yellow oil; 10.00 g. 31…”

“…Colorless oil: 14.00 g. 31 3S,4R,5S,6R) were multiplied by a factor of six to account for the dilution during the hydrolysis step.…”

“…Standard procedure in 32 %, yield as a mixture of RP and SP diastereoisomers as  and  anomers. Light yellow oil; 0.23 g 31. P-NMR (202 MHz, CDCl3): δP 2.36 (0.3P), 2.03 (1P), 1.90 (0.4P) ppm.…”

Expedient synthesis and biological evaluation of alkenyl acyclic nucleoside phosphonate prodrugs

“…2,10,11 Given the tremendous importance of phosphor(n)oamidate prodrugs in the antiviral arena and beyond, after the approval of Sofosbuvir and TAF, the application of the ProTide technology has grown dramatically and it has started to show very promising results in other therapeutic areas as well. [12][13][14] While there are several efficient procedures to synthesize phosphoroamidate nucleosides, the phosphonoamidate cognate class especially of acyclic nucleoside phosphonates (ANPs) lacks of such plethora of synthetic methodologies. 15 ANPs play a key role in the treatment of viral infections, and this class of compounds can be regarded as one of the most significant group of drugs in the antiviral field.…”