Clinical Pipelines for Alzheimer's Disease Psychosis and Agitation.

Agitation and psychosis are key behavioral and psychological symptoms of Alzheimer's disease (AD). For family and caregivers of patients, such symptoms are critical factors of distress and increased burden, but medication to treat them is limited. In most cases, drugs for other neuropsychiatric diseases have been used to manage these symptoms in an off-label manner. Due to the complex pathological background of AD and limited clinical data, obtaining proof of concept for the treatment of these symptoms is challenging. However, in 2023, the U.S. Food and Drug Administration approved brexpiprazole as the first and only drug to treat agitation in AD. Several other compounds have been evaluated in clinical situations. This review highlights recent pipelines being developed for agitation and psychosis for patients living with AD.

A Quantum Mechanics-Based Method to Predict Intramolecular Hydrogen Bond Formation Reflecting P-glycoprotein Recognition.

Passive membrane permeability and an active transport process are key determinants for penetrating the blood-brain barrier. P-glycoprotein (P-gp), a well-known transporter, serves as the primary gatekeeper, having broad substrate specificity. A strategy to increase passive permeability and impair P-gp recognition is intramolecular hydrogen bonding (IMHB). 3 is a potent brain penetrant BACE1 inhibitor with high permeability and low P-gp recognition, although slight modifications to its tail amide group significantly affect P-gp efflux. We hypothesized that the difference in the propensity to form IMHB could impact P-gp recognition. Single-bond rotation at the tail group enables both IMHB forming and unforming conformations. We developed a quantum-mechanics-based method to predict IMHB formation ratios (IMHBRs). In a given data set, IMHBRs accounted for the corresponding temperature coefficients measured in NMR experiments, correlating with P-gp efflux ratios. Furthermore, the method was applied in hNK2 receptor antagonists, demonstrating that the IMHBR could be applied to other drug targets involving IMHB.

Stereoselective Synthesis of Tricyclic ß-Lactam by Sulfoxide-Directed Oxidative Lactonization from an Accessible Cephalosporin Intermediate.

Tricyclic ß-lactam antibiotics show significant antibacterial activities against carbapenem-resistant Enterobacterales (CREs), but the synthesis of a key intermediate for tricyclic ß-lactam antibiotics requires eight steps from penicillin with a low total yield of 3% via non-stereoselective lactone formation. Here we report the stereoselective synthesis of the tricyclic ß-lactam core by sulfoxide-directed oxidative lactonization from an accessible and inexpensive commercially available cephalosporin intermediate in 23% total yield in six steps.

Concise syntheses of GB22, GB13, and himgaline by cross-coupling and complete reduction.

Neuroactive metabolites from the bark of Galbulimima belgraveana occur in variable distributions among trees and are not easily accessible through chemical synthesis because of elaborate bond networks and dense stereochemistry. Previous syntheses of complex congeners such as himgaline have relied on iterative, stepwise installation of multiple methine stereocenters. We decreased the synthetic burden of himgaline chemical space to nearly one-third of the prior best (7 to 9 versus 19 to 31 steps) by cross-coupling high fraction aromatic building blocks (high Fsp2) followed by complete, stereoselective reduction to high fraction sp3 products (high Fsp3). This short entry into Galbulimima alkaloid space should facilitate extensive chemical exploration and biological interrogation.

Discovery of a Tricyclic ß-Lactam as a Potent Antimicrobial Agent against Carbapenem-Resistant Enterobacterales, Including Strains with Reduced Membrane Permeability and Four-Amino Acid Insertion into Penicillin-Binding Protein 3: Structure-Activity-Relationships and In Vitro and In Vivo Activities.

The current worldwide emergence of carbapenem-resistant enterobacterales (CREs) constitutes an important growing clinical and public health threat. Acquired carbapenemases are the most important determinants of resistance to carbapenems. In the development of the previously reported tricyclic ß-lactam skeleton which exhibits potent antibacterial activities against several problematic ß-lactamase-producing CREs without a ß-lactamase inhibitor, we found that these activities were reduced against clinical isolates with resistance mechanisms other than ß-lactamase production. These mechanisms were the reduction of outer membrane permeability with the production of ß-lactamases and the insertion of four amino acids into penicillin-binding protein 3. Here, we report the discovery of a potent compound that overcomes these resistance mechanisms by the conversion of the alkoxyimino moiety of the aminothiazole side chain in which a hydrophilic functional group is introduced and the carboxylic acid of the alkoxyimino moiety is converted to reduce the negative charge of the whole molecule from 2 to 1. This potent tricyclic ß-lactam is a promising drug candidate for infectious diseases caused by CREs due to its potent therapeutic efficacy in the neutropenic mouse lung infection model and low frequency of producing spontaneously resistant mutants.

A novel tricyclic ß-lactam exhibiting potent antibacterial activities against carbapenem-resistant Enterobacterales: Synthesis and structure-activity-relationships.

A series of tricyclic ß-lactams were synthesized and evaluated for in vitro antibacterial activities against carbapenem-resistant Enterobacterales (CREs). Starting from a reported tricyclic ß-lactam that combined the cephalosporin skeleton having a γ-lactone ring with a carboxylic acid group, which was reported as a unique partial structure of Lactivicin, we identified the compound which shows potent antibacterial activities against all tested CREs by introducing sulfoxide. In addition, the sulfoxide-introduced tricyclic ß-lactam also shows a strong therapeutic efficacy in the neutropenic mouse lung infection model. These results indicate that the tricyclic ß-lactam skeleton will show sufficient therapeutic performance in clinical use and therefore can serve as a scaffold in the search for new antibacterial agents against CREs.

Discovery of Atabecestat (JNJ-54861911): A Thiazine-Based ß-Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor Advanced to the Phase 2b/3 EARLY Clinical Trial.

Accumulation of amyloid ß peptides (Aß) is thought to be one of the causal factors of Alzheimer's disease (AD). The aspartyl protease ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting protease for Aß production, and therefore, BACE1 inhibition is a promising therapeutic approach for the treatment of AD. Starting with a dihydro-1,3-thiazine-based lead, Compound J, we discovered atabecestat 1 (JNJ-54861911) as a centrally efficacious BACE1 inhibitor that was advanced into the EARLY Phase 2b/3 clinical trial for the treatment of preclinical AD patients. Compound 1 demonstrated robust and dose-dependent Aß reduction and showed sufficient safety margins in preclinical models. The potential of reactive metabolite formation was evaluated in a covalent binding study to assess its irreversible binding to human hepatocytes. Unfortunately, the EARLY trial was discontinued due to significant elevation of liver enzymes, and subsequent analysis of the clinical outcomes showed dose-related cognitive worsening.

Trifluoromethyl Dihydrothiazine-Based ß-Secretase (BACE1) Inhibitors with Robust Central ß-Amyloid Reduction and Minimal Covalent Binding Burden.

The ß-site amyloid precursor protein cleaving enzyme 1 (BACE1, also known as ß-secretase) is a promising target for the treatment of Alzheimer's disease. A pKa lowering approach over the initial leads was adopted to mitigate hERG inhibition and P-gp efflux, leading to the design of 6-CF3 dihydrothiazine 8 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide). Optimization of 8 led to the discovery of 15 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-(fluoromethoxy)pyrazine-2-carboxamide) with an excellent balance of potency, hERG inhibition, P-gp efflux, and metabolic stability. Oral administration of 8 elicited robust Aß reduction in dog even at 0.16 mg/kg. Reflecting the reduced hERG inhibitory activity, no QTc prolongation was observed at high doses. The potential for reactive metabolite formation of 15 was realized in a nucleophile trapping assay using [14 C]-KCN in human liver microsomes. Utilizing covalent binding (CVB) in human hepatocytes and the maximum projected human dosage, the daily CVB burden of 15 was calculated to be at an acceptable value of below 1 mg/day. However, hepatotoxicity was observed when 15 was subjected to a two-week tolerance study in dog, which prevented further evaluation of this compound.

Synthesis of a 6-CF3-Substituted 2-Amino-dihydro-1,3-thiazine ß-Secretase Inhibitor by N, N-Diethylaminosulfur Trifluoride-Mediated Chemoselective Cyclization.

The synthesis of a 6-CF3-substituted 2-amino-dihydro-1,3-thiazine via N, N-diethylaminosulfur trifluoride (DAST)-mediated cyclization of N-hydroxypropyl thiourea 6 is described. This reaction gave 6-CF3-1,3-thiazine 7 with high chemical yield and chemoselectivity, suppressing the common byproduct of oxazine 8. This new protocol enabled access to 6-CF3-substituted 1,3-thiazine ß-secretase inhibitor 2.

Branch-Selective Addition of Unactivated Olefins into Imines and Aldehydes.

Radical hydrofunctionalization occurs with ease using metal-hydride hydrogen atom transfer (MHAT) catalysis to couple alkenes and competent radicalophilic electrophiles. Traditional two-electron electrophiles have remained unreactive. Herein we report the reductive coupling of electronically unbiased olefins with imines and aldehydes. Iron catalysis allows addition of alkyl-substituted olefins into imines through the intermediacy of free radicals, whereas a combination of catalytic Co(Sal t-Bu, t-Bu) and chromium salts enables a branch-selective coupling of olefins and aldehydes through the formation of a putative alkyl chromium intermediate.

Iron-catalysed asymmetric tandem spiro-cyclization using dioxygen in air as the hydrogen acceptor.

A tandem combination of ortho-quinone methide (o-QM) formation/Michael addition/asymmetric dearomatization, which is catalysed by an iron-salan complex in air with high enantioselectivity, provides an efficient method for spirocyclic (2H)-dihydrobenzofuran synthesis from 2-naphthols and phenols. The key to the success of the tandem synthesis is the development of aerobic oxidative o-QM formation.

Iron-catalyzed dioxygen-driven C-C bond formation: oxidative dearomatization of 2-naphthols with construction of a chiral quaternary stereocenter.

Iron(salan) complex 1 was found to catalyze the oxidative dearomatization of 1-substituted 2-naphthols with the formation of an all-carbon quaternary stereocenter in air in the presence of nitroalkanes, to afford the corresponding cyclic enones with high enantioselectivity of 88-96% ee.

What factors influence the catalytic activity of iron-salan complexes for aerobic oxidative coupling of 2-naphthols?

A few Fe-salan dimer complexes serve as catalysts for aerobic oxidative coupling (AOC) of 2-naphthols, but some others do not. X-Ray and cyclic voltammetry studies of various Fe-salan complexes revealed that the absence or the presence of double hydrogen bonding in Fe-salan dimers, the oxidation potential of monomeric Fe-salan species and the location of the resulting radical cation are critical factors for the catalytic activity of iron-salan complexes for the AOC.

Aerobic oxidative kinetic resolution of secondary alcohols with naphthoxide-bound iron(salan) complex.

The first general method for iron-catalyzed aerobic oxidative kinetic resolution of secondary alcohols was achieved with good to high enantiomeric differentiation (k(rel) = 7-50). Although iron(salan) complex 1 does not catalyze alcohol oxidation, the naphthoxide-bound iron(salan) complex does.

Enantioenriched synthesis of C1-symmetric BINOLs: iron-catalyzed cross-coupling of 2-naphthols and some mechanistic insight.

Highly enantioselective aerobic oxidative cross-coupling of 2-naphthols with broad substrate scope was achieved using an iron(salan) complex as the catalyst. Enantiomeric excesses of the products ranged from 87 to 95%. The scope of the cross-coupling reaction was found to be different from that of the homocoupling reaction under the same reaction conditions.

Oxidation catalysis of Nb(salan) complexes: asymmetric epoxidation of allylic alcohols using aqueous hydrogen peroxide as an oxidant.

Several optically active Nb(salan) complexes were synthesized, and their oxidation catalysis was examined. A dimeric mu-oxo Nb(salan) complex that was prepared from Nb(OiPr)(5) and a salan ligand was found to catalyze the asymmetric epoxidation of allylic alcohols using a urea-hydrogen peroxide adduct as an oxidant with good enantioselectivity. However, subsequent studies of the time course of this epoxidation and of the relationship between the ee of the ligand and the ee of the product indicated that the mu-oxo dimer dissociates into a monomeric species prior to epoxidation. Moreover, monomeric Nb(salan) complexes prepared in situ from Nb(OiPr)(5) and salan ligands followed by water treatment were found to catalyze the epoxidation of allylic alcohols better using aqueous hydrogen peroxide in CHCl(3)/brine or toluene/brine solution with high enantioselectivity ranging from 83 to 95% ee, except for the reaction of cinnamyl alcohol that showed a moderate ee of 74%. This is the first example of the highly enantioselective epoxidation of allylic alcohols using aqueous hydrogen peroxide as an oxidant.