Exploration of amino alcohol derivatives as novel, potent, and highly selective sphingosine-1-phosphate receptor subtype-1 agonists

Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

“…PPI-4955 (175)i sa na mino alcohol derivativet hat contains three key structural units:atrifluoromethyl-substituted phenyl ether,a ni midazole heterocycle, and ac hiral amino alcohol ( Figure 14). [64] It wasdiscovered by Praecis Pharmaceuticals and is the prodrug of ap otent and selectives phingosine-1-phosphate receptor-1 (S1P1) agonist (the primary alcohol is phosphorylated in vivo to give the active species), which is used as an immunosuppressant. Structure-activity relationship (SAR) studies demonstrated that incorporation of the CF 3 group improvedthe agonistselectivity for the S1P1 receptor.…”

“…Structure-activity relationship (SAR) studies demonstrated that incorporation of the CF 3 group improvedthe agonistselectivity for the S1P1 receptor. [64,65] The synthesis of 175 is described in Scheme 20 [64] and utilizes 1-…”

“…It was discovered by Praecis Pharmaceuticals and is the prodrug of a potent and selective sphingosine‐1‐phosphate receptor‐1 (S1P1) agonist (the primary alcohol is phosphorylated in vivo to give the active species), which is used as an immunosuppressant. Structure–activity relationship (SAR) studies demonstrated that incorporation of the CF 3 group improved the agonist selectivity for the S1P1 receptor …”

“…The synthesis of 175 is described in Scheme and utilizes 1‐[4‐fluoro‐3‐(trifluoromethyl)phenyl]ethanone ( 176 ) as the starting material. A nucleophilic substitution reaction (S N Ar) between 176 and alcohol 177 with t BuOK as the base afforded substituted acetophenone 178 .…”

Discovery of Clinical Candidate GSK1842799 As a Selective S1P1 Receptor Agonist (Prodrug) for Multiple Sclerosis

“…12 One major challenge in the prodrug strategy in S1P activation is its in vivo phosphorylation of the prodrug to the desired phospho-drug since this process requires prodrug phosphorylation with either SphK1 or SphK2, while the phospho-drug could be converted back to the starting prodrug through the action of sphingosine-1-phosphate phosphatase 1 (S1PP1), sphingosine-1-phosphate phosphatase 2 (S1PP2), or a potential lipid phosphate phosphatase. 13 In our most recent prodrug publication, 10 we reported on preclinical candidate PPI-4955 (Table 1) and its phosphorylation outcome in rodent models. In an effort to establish a backup molecule to PPI-4955 with improved profile especially in in vivo phosphorylation, we carried out further structure−activity relationship (SAR) studies with a focus on sphingosine kinase activity and in vivo phosphorylation relationships.…”