ABSTRACT
The discovery of a new series of selective S1P1 agonists is described. This series of piperazinyl-oxadiazole derivatives was rapidly optimized starting from high-throughput screening hit 1 to afford potent and selective lead compound 10d. Further SAR studies showed that 10d was converted to the active phosphate metabolite 29 in vivo. Oral administration of compound 10d to rats was shown to induce lymphopenia at 3 mg/kg.
Subject(s)
Oxadiazoles/pharmacology , Piperazines/pharmacology , Receptors, Lysosphingolipid/agonists , Administration, Oral , Animals , Dose-Response Relationship, Drug , Female , Lymphopenia/chemically induced , Lymphopenia/pathology , Molecular Structure , Oxadiazoles/administration & dosage , Oxadiazoles/chemistry , Piperazines/administration & dosage , Piperazines/chemistry , Rats , Rats, Inbred Lew , Sphingosine-1-Phosphate Receptors , Structure-Activity RelationshipABSTRACT
The regio- and stereoselectivity of intramolecular [2 + 2] photocycloadditions of 2'-hydroxyenones are shown to be solvent-dependent. In the presence of aprotic solvents, 2'-hydroxyenones undergo photocycloadditions in a manner consistent with the presence of an intramolecular hydrogen bond between the carbonyl group and the tether's hydroxy functionality. In protic solvents, intermolecular interactions appear to disrupt the intramolecular hydrogen bond, providing products with complementary diastereoselectivity. If the facial accessibility of the alpha-tethered olefin is limited, the cycloadditions proceed to give head-to-tail or head-to-head regioisomers, depending on the nature of the solvent employed.
Subject(s)
Alkenes/chemistry , Ketones/chemistry , Solvents/chemistry , Cyclization , Cyclobutanes/chemistry , Hydrogen Bonding , Molecular Structure , Oxidation-Reduction , Photochemistry , StereoisomerismABSTRACT
[reaction: see text] The intramolecular Diels-Alder reaction of 5-vinyl-1,3-cyclohexadienes affording substituted tricyclo[3.2.1.0(2,7)]oct-3-enes is studied.
