title: 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.
abstract: 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 alpha-, beta-, and gamma-secretases. As the latter two contribute to the formation of neurotoxic Abeta fragments while alpha-secretase does not, a decrease in the amyloidogenic products can be brought about either by inhibition of the beta- and gamma-secretases or through the activation of alpha-secretase. It is now known that the activation of protein kinase C (PKC) enhances alpha-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 PKCalpha. 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 13, suggesting adverse electronic interactions of the sulfur atom with PKC or parts of the cellular membrane.
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 S. Wood St., Chicago, Illinois 60612, USA.
authors.forename: Ulrich R
authors.initials: UR
authors.lastname: Mach
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lewin
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D007769:Lactams; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011493:Protein Kinase C