ABSTRACT
By use of iterative design aided by predictive models for target affinity, brain permeability, and hERG activity, novel and diverse compounds based on cyclic amidine and guanidine cores were synthesized with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease. Since synthesis feasibility had low priority in the design of the cores, an extensive synthesis effort was needed to make the relevant compounds. Syntheses of these compounds are reported, together with physicochemical properties and structure-activity relationships based on in vitro data. Four crystal structures of diverse amidines binding in the active site are deposited and discussed. Inhibitors of BACE-1 with 3 µM to 32 nM potencies in cells are shown, together with data on in vivo brain exposure levels for four compounds. The results presented show the importance of the core structure for the profile of the final compounds.
Subject(s)
Amidines/chemical synthesis , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Guanidines/chemical synthesis , Amidines/chemistry , Amidines/pharmacology , Amyloid Precursor Protein Secretases/chemistry , Animals , Aspartic Acid Endopeptidases/chemistry , Brain/metabolism , CHO Cells , Cell Line, Tumor , Cell Membrane Permeability , Computer Simulation , Cricetinae , Crystallography, X-Ray , Dogs , Drug Stability , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Female , Guanidines/chemistry , Guanidines/pharmacology , Humans , Madin Darby Canine Kidney Cells , Mice , Mice, Inbred C57BL , Protein Conformation , Quantitative Structure-Activity Relationship , StereoisomerismABSTRACT
A series of bis(terpyridine)RuII complexes have been prepared, where one of the terpyridines is functionalized in the 4'-position by a phosphonic or carboxylic acid group for attachment to TiO2. The other is functionalized, also in the 4'-position, by a potential electron donor. In complexes 1a, 3a, and 4a,b, this donor is tyrosine or hydrogen-bonded tyrosine, while in 2a it is carotenoic amide. The synthesis and photophysical properties of the complexes are discussed. On irradiation with visible light, the formation of a long-lived charge-separated state was anticipated, via primary electron ejection into the TiO2, followed by secondary electron transfer from the donor to the photogenerated RuIII. However, such a charge-separated state could be observed with certainty only with complex 2a. To explain the result, quantum chemical calculations were performed on the different types of complexes.
ABSTRACT
The preparation of donor (D)-photosensitizer (S) arrays, consisting of a manganese complex as D and a ruthenium tris(bipyridyl) complex as S has been pursued. Two new ruthenium complexes containing coordinating sites for one (2a) and two manganese ions (3a) were prepared in order to provide models for the donor side of photosystem II in green plants. The manganese coordinating site consists of bridging and terminal phenolate as well as terminal pyridyl ligands. The corresponding ruthenium-manganese complexes, a manganese monomer 2b and dimer 3b, were obtained. For the dimer 3b, our data suggest that intramolecular electron transfer from manganese to photogenerated ruthenium(III) is fast, k(ET) > 5 x 10(7) s(-)(1).