Novel aryl-fused sphingolipids, in which aryl-/heteroaryl-moieties were incorporated into the allylic 4,5,6-positions of sphingosine, were prepared and found to possess good in vitro PKC inhibitory activity. (3-(1-Dodecynyl)phenyl)- and (4- and (5-(1-dodecynyl)-2-thienyl)-2-amino-l,3-propanediols were found to have topical antiinflammatory activity comparable to sphingosine.Protein kinase C (PKC) is a major player in signal transduction and the regulation of numerous cellular processes. 1 Evidence demonstrating alterations in the PKC signal transduction system in psoriasis has been reviewed. 2 The natural product sphingosine, D(+)-erythro-l,3-dihydroxy-2-amino-4-trans-octadecene (1), and related long-chain bases have PKC inhibitory properties. 3 Sphingoid bases also displayed in vitro antiinflammatory properties in human neutrophils. 4 In vivo studies confirmed the ability of topically applied sphingosine to reduce phorbol ester-induced inflammation and epidermal hyperplasia and suggested its potential for the treatment of psoriasis and other inflammatory skin disorders. 5 With this in mind, we undertook a program to identify novel topically effective PKC inhibitors. With the knowledge that novel 1,3-pyridinyl-fused LTB 4 analogs 6 had displayed interesting biological properties, we initiated our studies with the synthesis and evaluation of a series of 1,3-pyfidinyl-fused sphingosine derivatives (2). This report reveals the promising in vitro PKC inhibitory activity found in these and numerous other aryl- and heteroaryl- derivatives (3-7) and the topical antiinflammatory activity displayed by several lead compounds.