The primary cause of Alzheimer’s disease (AD) is the accumulation of amyloid-beta (Abeta) peptide aggregates in brain. Various Abeta aggregation inhibitory peptides such as the KLVFF peptide derived from the Abeta sequence have been developed. These peptides are considered as potential candidates for therapeutic agents of AD with high potency and safety. However, their low physiological stability and high aggregability pose significant challenges to their clinical application. In this study, we focused on the design and synthesis of chloroalkene dipeptide isosteres (CADIs), because a chloroalkene moiety functions as a chemical equivalent of a peptide bond. CADIs are rationally designed based on the structural homology between chlorine and oxygen atoms in terms of van der Waals radii, and the electronic homology of them in their electronegativity and the alignment of the dipole moment vector of the chloroalkene moiety and the peptide bond.1,2 Therefore, CADI is considered as an ideal isostere of a peptide bond. Herein, we successfully synthesized CADIs via diastereoselective allylic alkylation of (Z)-gamma, gamma-dichloro-alpha, beta-unsaturated ester with organocopperzinc reagents.3,4 The resulting CADIs were incorporated into the KLVFF peptide using solid-phase peptide synthesis, followed by resin cleavage, cyclization, and deprotection to afford cyclic peptidomimetics. The inhibitory activity of the CADI-containing cyclo [KLVFF] against Abeta aggregation was evaluated.5,6 As a result, these peptidomimetics showed the improved inhibitory activity against Abeta aggregation compared to the parent peptide. Furthermore, a dimeric form consisting of ten amino acid residues exhibited even stronger inhibition of Abeta aggregation. 6 In this presentation, we will discuss the details of design, synthesis, and biological evaluation of the CADI-containing Abeta aggregation inhibitor peptides.