Alzheimer’s disease is the most common cause of dementia. According to the amyloid hypothesis, β-secretase (BACE1) is a promising molecular target for the development of anti-Alzheimer’s disease drugs. BACE1 triggers the formation of the amyloid-β (Aβ) peptides that are the main component of senile plaques in the brain of patients with Alzheimer’s disease. As BACE1 cleaves the amyloid precursor protein at the N-terminus of the Aβ domain, BACE1 inhibitors reduce the Aβ level in the brain. Previously, we designed a series of peptidic inhibitors that possessed a substrate transition-state analogue, and the structure-activity relationship of our inhibitors was evaluated, based on docking and scoring, using the docking simulation software Molecular Operating Environment (MOE). However, there was no association between the scoring values and the inhibitory activities at the P2 position. Hence, we hypothesized that the interaction of the P2 position of the inhibitor with the S2 site of BACE1 was critical for the mechanism of inhibition, and we proposed the novel concept of ‘electron donor bioisostere’ for drug discovery. Using this concept, we designed potent small molecule non-peptidic BACE1 inhibitors.
Part of the book: Quantitative Structure-activity Relationship
Pyridine is a unique aromatic ring. Although pyridines are used industrially, pyridine moieties are present in many natural products, such as vitamins, coenzymes, and alkaloids, and also in many drugs and pesticides. Pyridine moieties are often used in drugs because of their characteristics such as basicity, water solubility, stability, and hydrogen bond-forming ability, and their small molecular size. Because pyridine rings are able to act as the bioisosteres of amines, amides, heterocyclic rings containing nitrogen atoms, and benzene rings, their replacement by pyridine moieties is important in drug discovery. Recently, we synthesized a series of BACE1 inhibitors by in silico conformational structure-based drug design and found an important role of pyridine moiety as a scaffold. In this chapter, we describe the important role of pyridines in medicinal chemistry and the development of β-secretase inhibitors possessing a pyridine scaffold for the treatment of Alzheimer’s disease.
Part of the book: Pyridine
Peptides or small-size proteins are important substances for medicines, diagnosis, and molecular biology research. In organic synthesis, the peptide bonds formation is performed in an organic solution (liquid-phase peptide synthesis, LPPS), or on a resin (solid-phase peptides synthesis, SPPS). LPPS can prepare a high volume of peptides, but it is generally required long processes and high cost for peptides preparation and is not appropriate for long-chain peptides. SPPS can prepare long-chain peptides until 40 residues in a short time. However, it is difficult to obtain the pure peptides because of no purification of its intermediates. For a solution of these problems, Kent et al. reported native chemical ligation (NCL) method for the preparation of long-chain peptides. Because peptides with a long chain or difficult sequence formed β-sheet structure within a molecule, these peptides have high aggregability and low solubility, and their preparation and purification are generally difficult. Mutter et al. reported ‘pseudoproline’ method for difficult sequence-containing peptide preparation. We previously reported a series of prodrugs based on O-N intramolecular acyl migration. We reported ‘O-isoacylpeptide’ method for the preparation of difficult sequence-containing peptides using the prodrug strategy based on O-N intramolecular acyl migration.
Part of the book: Peptide Synthesis