Mild Cognitive Impairment Patients Have Higher Regulatory T-Cell Proportions Compared With Alzheimer's Disease-Related Dementia Patients.

Objectives: The role of neuroinflammation in the pathogenesis of Alzheimer's disease (AD) has attracted much attention recently. Regulatory T-cells (Tregs) play an important role in modulating inflammation. We aimed to explore the Treg-related immunosuppression status at different stages of AD. Methods: Thirty healthy control (HC) subjects, 26 patients with mild cognitive impairment (MCI), 30 patients with mild probable AD-related dementia, and 28 patients with moderate-to-severe probable AD-related dementia underwent detailed clinical history taking, structural MRI scanning, and neuropsychological assessment. Peripheral blood samples were taken to measure the percentage of CD4+CD25+CD127low/- Tregs by flow cytometry and the levels of interleukin (IL-10), interleukin (IL-35), and transforming growth factor ß (TGF-ß) by ELISA. Results: The percentage of Tregs in the blood of MCI patients was the highest (9.24%); there was a significant difference between patients with MCI and patients with probable AD-related dementia. The level of TGF-ß in patients with MCI (47.02 ng/ml) was significantly increased compared with patients with AD-related dementia. There were positive correlations between Treg percentage, IL-35, and Mini-mental state evaluation scores in patients with MCI and probable AD-related dementia. Conclusions: Patients with MCI have stronger Treg-related immunosuppression status compared with patients with probable AD-related dementia.

Application of Virtual Screening to the Identification of New LpxC Inhibitor Chemotypes, Oxazolidinone and Isoxazoline.

This report summarizes the identification and synthesis of novel LpxC inhibitors aided by computational methods that leveraged numerous crystal structures. This effort led to the identification of oxazolidinone and isoxazoline inhibitors with potent in vitro activity against P. aeruginosa and other Gram-negative bacteria. Representative compound 13f demonstrated efficacy against P. aeruginosa in a mouse neutropenic thigh infection model. The antibacterial activity against K. pneumoniae could be potentiated by Gram-positive antibiotics rifampicin (RIF) and vancomycin (VAN) in both in vitro and in vivo models.

Development of a cyclosporin A derivative with excellent anti-hepatitis C virus potency.

Synthetic modification of cyclosporin A at P3-P4 positions led to the discovery of NIM258, a next generation cyclophilin inhibitor with excellent anti-hepatitis C virus potency, with decreased transporter inhibition, and pharmacokinetics suitable for coadministration with other drugs. Herein is disclosed the evolution of the synthetic strategy to from the original medicinal chemistry route, designed for late diversification, to a convergent and robust development synthesis. The chiral centers in the P4 fragment were constructed by an asymmetric chelated Claisen rearrangement in the presence of quinidine as the chiral ligand. Identification of advanced crystalline intermediates enabled practical supply of key intermediates. Finally, macrocyclization was carried out at 10% weight concentration by a general and unconventional "slow release" concept.

Potent nonimmunosuppressive cyclophilin inhibitors with improved pharmaceutical properties and decreased transporter inhibition.

Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.

Design and synthesis of lactam-thiophene carboxylic acids as potent hepatitis C virus polymerase inhibitors.

Herein we report the successful incorporation of a lactam as an amide replacement in the design of hepatitis C virus NS5B Site II thiophene carboxylic acid inhibitors. Optimizing potency in a replicon assay and minimizing potential risk for CYP3A4 induction led to the discovery of inhibitor 22a. This lead compound has a favorable pharmacokinetic profile in rats and dogs.

From chemical tools to clinical medicines: nonimmunosuppressive cyclophilin inhibitors derived from the cyclosporin and sanglifehrin scaffolds.

The cyclophilins are widely expressed enzymes that catalyze the interconversion of the cis and trans peptide bonds of prolines. The immunosuppressive natural products cyclosporine A and sanglifehrin A inhibit the enzymatic activity of the cyclophilins. Chemical modification of both the cyclosporine and sanglifehrin scaffolds has produced many analogues that inhibit cyclophilins in vitro but have reduced immunosuppressive properties. Three nonimmunosuppressive cyclophilin inhibitors (alisporivir, SCY-635, and NIM811) have demonstrated clinical efficacy for the treatment of hepatitis C infection. Additional candidates are in various stages of preclinical development for the treatment of hepatitis C or myocardial reperfusion injury. Recent publications suggest that cyclophilin inhibitors may have utility for the treatment of diverse viral infections, inflammatory indications, and cancer. In this review, we document the structure-activity relationships of the nonimmunosuppressive cyclosporins and sanglifehrins in clinical and preclinical development. Aspects of the pharmacokinetic behavior and chemical biology of these drug candidates are also described.

Chiral phosphoramide-catalyzed enantioselective addition of allylic trichlorosilanes to aldehydes. Preparative and mechanistic studies with monodentate phosphorus-based amides.

The addition of allylic trichlorosilanes to benzaldehyde promoted by chiral phosphoramides to give the enantioenriched homoallylic alcohol has been investigated. In a survey of Lewis bases as activators for the addition of allyltrichlorosilane to benzaldehyde, phosphorus-based amides have been found to be the most effective promoters. To achieve asymmetric induction, chiral phosphoric triamides derived from chiral diamines have been developed and applied in the allylation reaction albeit with modest enantioselectivities. The addition of 2-butenylsilanes was highly diastereoselective, suggesting a closed, chair-like transition structure. A detailed mechanistic study has been carried out to probe into the origin of activation. From a combination of nonlinear effects and kinetics studies, the reaction was found to likely involve two phosphoramides in both the rate and stereochemistry determining steps. These studies provided the background for the development of highly selective and reactive catalysts.

Chiral phosphoramide-catalyzed enantioselective addition of allylic trichlorosilanes to aldehydes. Preparative studies with bidentate phosphorus-based amides.

On the basis of the mechanistic insight that more than one Lewis basic moiety (phosphoramide) is involved in the rate- and stereochemistry-determining step of enantioselective allylation, bidentate chiral phosphoramides were developed. Different chiral phosphoramide moieties were connected by tethers of methylene chains of varying length. The rate and enantioselectivity of allylation with allyltrichlorosilane promoted by the bidentate phosphoramides was found to be highly dependent on the tether length. A new phosphoramide based on a 2,2'-bispyrrolidine skeleton has been designed and afforded good yield, efficient turnover, and high enantioselectivity in allylation reactions. The synthesis of enantiopure 2,2'-bispyrrolidine was easily accomplished on large scale by photodimerization of pyrrolidine followed by resolution with L(or D)-tartaric acid. The scope of the allylation reaction was examined with variously substituted allylic trichlorosilanes and unsaturated aldehydes. This method has been applied to the construction of stereogenic, quaternary centers by the addition of unsymmetrically gamma-disubstituted allylic trichlorosilanes.

Understanding the correlation of structure and selectivity in the chiral-phosphoramide-catalyzed enantioselective allylation reactions: solution and solid-state structural studies of bisphosphoramide.SnCl(4) complexes.

Complexation of bisphosphoramides, linked by various length methylene tethers, with tin tetrachloride was studied by both solution NMR spectroscopy and single-crystal X-ray crystallography. The formation of cis-configured, octahedral 1/1 bisphosphoramide.SnCl(4) complexes was supported by both crystallographic and solution NMR studies. In addition, the formation of such complexes was shown to be highly dependent on the tether length and solution concentration. Single-crystal X-ray analysis of bisphosphoramide.SnCl(4) complexes also provided detailed information on the stereochemical environment relevant to the enantioselectivity of asymmetric allylation reactions.

Catalytic enantioselective allylation with chiral Lewis bases.

The advent of chiral Lewis base-promoted allylation of aldehydes has opened a new direction in the catalytic enantioselective construction of homoallylic alcohols. This short review outlines the conceptual framework for the creation of this new process and the interplay of mechanistic investigations and synthetic studies that have conspired to produce a useful new reaction. The current state-of-the-art in catalyst design and application of the reaction in synthesis are briefly illustrated.

Asymmetric construction of quaternary centers by enantioselective allylation: application to the synthesis of the serotonin antagonist LY426965.

[reaction: see text] Catalytic enantioselective allylation with a chiral bisphosphoramide was applied to the synthesis of LY426965, a serotonin antagonist. The key step, addition of a 3,3-disubstituted allyltrichlorosilane to benzaldehyde, provided the adduct containing a stereogenic quaternary center with excellent diastereoselectivity and enantioselectivity.