Synthesis and Pharmacological Evaluation of 8‐ and 9‐Substituted Benzolactam‐V8 Derivatives as Potent Ligands for Protein Kinase C, a Therapeutic Target for Alzheimer's Disease

<jats:title>Abstract</jats:title><jats:p>A central element in the pathophysiology of Alzheimer's disease (AD) is the formation of amyloid plaques, which result from abnormal processing of the amyloid precursor protein (APP). The processing of APP is largely provided by three key enzymes, namely the α‐, β‐, and γ‐secretases. As the latter two contribute to the formation of neurotoxic Aβ fragments while α‐secretase does not, a decrease in the amyloidogenic products can be brought about either by inhibition of the β‐ and γ‐secretases or through the activation of α‐secretase. It is now known that the activation of protein kinase C (PKC) enhances α‐secretase activity and therefore represents a possible target for the development of agents urgently needed for the treatment of this devastating neurodegenerative disorder. In the present study, new benzolactam‐V8‐based PKC activators were synthesized and tested for their binding affinity toward PKCα. All compounds tested showed binding values in the nanomolar concentration range. In accordance with previous publications, 9‐substitution dramatically increased PKC binding affinity in comparison with the corresponding 8‐substituted analogues. In addition to the location of the side chain on the aromatic ring, the binding affinities of these benzolactams were found to depend on the orientation, length, and electronic properties of this appendage. An interesting decrease in binding affinity was found for the 9‐thienyl analogue <jats:bold>13</jats:bold>, suggesting adverse electronic interactions of the sulfur atom with PKC or parts of the cellular membrane.</jats:p>