Protein kinase C (PKC) is known to participate in the processing of the amyloid precursor protein (APP). Abnormal processing of APP through the action of the β- and γ-secretases leads to the production of the 39−43 amino acid Aβ fragment, which is neurotoxic and which is believed to play an important role in the etiology of Alzheimer's disease. PKC activation enhances α-secretase activity, which results in a decrease of the amyloidogenic products of β-secretase. In this article, we describe the synthesis of 10 new benzolactam V8 based PKC activators having side chains of varied saturation and lipophilicity linked to the aromatic ring through an amide group. The K_i values measured for the inhibition of phorbol ester binding to PKCα are in the nanomolar range and show some correlation with their lipophilicity. Compounds 5g and 5h show the best binding affinity among the 10 benzolactams that were synthesized. By use of a cell line derived from an AD patient, significant enhancement of sAPPα secretion was achieved at 1 μM concentration for most of the compounds studied and at 0.1 μM for compounds 5e and 5f. At 1 μM the enhancement of sAPPα secretion for compounds 5c−h is higher than that observed for the control compound 8-(1-decynyl)benzolactam (BL). Of interest is the absence of activity found for the highly lipophilic ligand 5i, which has a K_iof 11 nM. On the other hand, its saturated counterpart 5j, which possesses a comparable K_i and ClogP, retains activity in the secretase assay. In the hyperplasia studies, 5f showed a modest response at 100 μg and 5e at 300 μg, suggesting that 5f was approximately 30-fold less potent than the PKC activator mezerein and 100-fold less potent than TPA. 5e was approximately 3-fold less active than 5f. On the basis of the effect of unsaturation for other potent PKC ligands, we would predict that 5e would retain biological activity in most assays but would show a marked loss of tumor-promoting activity. Compound 5e thus becomes a viable candidate compound in the search for Alzheimer's therapeutics capable of modulating amyloid processing.