Macrocyclic BACE1 inhibitors with hydrophobic cross-linked structures: Optimization of ring size and ring structure.

Based on the X-ray crystallography of recombinant BACE1 and a hydroxyethylamine-type peptidic inhibitor, we introduced a cross-linked structure between the P1 and P3 side chains of the inhibitor to enhance its inhibitory activity. The P1 and P3 fragments bearing terminal alkenes were synthesized, and a ring-closing metathesis of these alkenes was used to construct the cross-linked structure. Evaluation of ring size using P1 and P3 fragments with various side chain lengths revealed that 13-membered rings were optimal, although their activity was reduced compared to that of the parent compound. Furthermore, the optimal ring structure was found to be a macrocycle with a dimethyl branched substituent at the P3 ß-position, which was approximately 100-fold more active than the non-substituted macrocycle. In addition, the introduction of a 4-carboxymethylphenyl group at the P1' position further improved the activity.

Applications of amide isosteres in medicinal chemistry.

Isosteric replacement of amide groups is a classic practice in medicinal chemistry. This digest highlights the applications of most commonly employed amide isosteres in drug design aiming at improving potency and selectivity, optimizing physicochemical and pharmacokinetic properties, eliminating or modifying toxicophores, as well as providing novel intellectual property of lead compounds.

Back to (non-)Basics: An Update on Neutral and Charge-Balanced Glycosidase Inhibitors.

Glycosidases have important anti-cancer, anti-viral and anti-diabetic properties. This review covers the literature in the past 15 years since our initial review in this journal on "neutral" glycosidase inhibitors lacking a basic nitrogen found in iminosugars and azasugars or inhibitors that are neutral by virtue of being "charge-balanced" (zwitterionic). These structurally diverse inhibitors include lactones, lactams, epoxides such as cyclophellitol, and sulfonium ion derivatives of the natural product salacinol. Synthetic efforts toward cyclophillitol, salicinol and derivatives are also highlighted. Importantly, certain metals can inhibit glycosidases and care must be taken to remove residual catalysts from synthetic material to be tested against these enzymes.

Evaluation of transition-state mimics in a superior BACE1 cleavage sequence as peptide-mimetic BACE1 inhibitors.

A superior substrate sequence for BACE1 containing transition-state mimics at the scissile site was evaluated as a protease inhibitor. Hydroxymethylcarbonyl (HMC) and hydroxyethylamine (HEA) isosteres were selected as the transition state mimics, and incorporated into the scissile site of the superior sequence covering the P4 to P1' sites (Glu-Ile-Thi-Thi(*)Nva; (*)denotes the cleavage site). Isosteres having different absolute configurations of the hydroxyl group were synthesized separately, and the effect of the configuration was evaluated. Configuration of the hydroxyl group of each isostere showed a marked effect on the inhibitory activity; anti-configuration to the scissile site substituent had potent inhibitory activity in an HMC-type inhibitor, whereas anti-configuration of HEA-type inhibitors showed no inhibitory activity. Structural evaluations based on X-ray crystallographic analyses of recombinant BACE1 in complex with each inhibitor provided insights into the protein-ligand interactions, especially at the prime sites.

Aspartic protease inhibitors containing tertiary alcohol transition-state mimics.

Aspartic proteases (APs) are a class of enzymes engaged in the proteolytic digestion of peptide substrates. APs play important roles in physiological and infectious pathways, making them plausible drug targets. For instance in the treatment of HIV infections, access to an efficient combination of protease and reverse transcriptase inhibitors have changed a terminal illness to a chronic but manageable disease. However, the benefits have been limited due to the emergence of drug resistant viral strains, poor pharmacokinetic properties of peptidomimetic inhibitors and adverse effects associated with the treatment. In the 1980s, D. Rich and co-workers proposed a novel strategy for the development of AP inhibitors by replacing the secondary hydroxyl group with a tertiary alcohol as part of the transition state (TS) mimicking moiety. This strategy has been extensively explored over the last decade with a common belief that masking of the polar group, e.g. by intramolecular hydrogen bonding, has the potential to enhance transcellular transport. This is the first review presenting the advances of AP inhibitors comprising a tertiary hydroxyl group. The inhibitors have been classified into different tert-hydroxy TS mimics and their design strategies, synthesis, biological activities, structure-activity-relationships and X-ray structures are discussed.