Fragment-Based Discovery of an Apolipoprotein E4 (apoE4) Stabilizer.

Apolipoprotein E is a 299-residue lipid carrier protein produced in both the liver and the brain. The protein has three major isoforms denoted apoE2, apoE3, and apoE4 which differ at positions 112 and 158 and which occur at different frequencies in the human population. Genome-wide association studies indicate that the possession of two apoE4 alleles is a strong genetic risk factor for late-onset Alzheimer's disease (LOAD). In an attempt to identify a small molecule stabilizer of apoE4 function that may have utility as a therapy for Alzheimer's disease, we carried out an NMR-based fragment screen on the N-terminal domain of apoE4 and identified a benzyl amidine based fragment binder. In addition to NMR, binding was characterized using various other biophysical techniques, and a crystal structure of the bound core was obtained. Core elaboration ultimately yielded a compound that showed activity in an IL-6 and IL-8 cytokine release assay.

Discovery of Novel Aminotetralines and Aminochromanes as Selective and Competitive Glycine Transporter 1 (GlyT1) Inhibitors.

The glycine transporter 1 (GlyT1) has emerged as a key novel target for the treatment of schizophrenia. Herein, we report the synthesis and biological evaluation of aminotetralines and aminochromanes as novel classes of competitive GlyT1 inhibitors. Starting from a high-throughput screening hit, structure-activity relationship studies led first to the discovery of aminotetralines displaying high GlyT1 potency and selectivity, with favorable pharmacokinetic properties. Systematic investigations of various parameters (e.g., topological polar surface area, number of hydrogen bond donors) guided by ex vivo target occupancy evaluation resulted in lead compounds possessing favorable brain penetration properties as for (7 S,8 R)-27a. Further optimization revealed compounds with reduced efflux liabilities as for aminochromane 51b. In an in vivo efficacy model (7 S,8 R)-27a, dose-dependently reversed L-687,414 induced hyperlocomotion in mice with an ED50 of 0.8 mg/kg. All these results suggest (7 S,8 R)-27a and 51b as new GlyT1 inhibitors worthy of further profiling.

De Novo Design, Synthesis, and Biological Evaluation of 3,4-Disubstituted Pyrrolidine Sulfonamides as Potent and Selective Glycine Transporter 1 Competitive Inhibitors.

The development of glycine transporter 1 (GlyT1) inhibitors may offer putative treatments for schizophrenia and other disorders associated with hypofunction of the glutaminergic N-methyl-d-aspartate (NMDA) receptor. Herein, we describe the synthesis and biological evaluation of a series of 3,4-disubstituted pyrrolidine sulfonamides as competitive GlyT1 inhibitors that arose from de novo scaffold design. Relationship of chemical structure to drug-drug interaction (DDI) and bioactivation was mechanistically investigated. Murine studies were strategically incorporated into the screening funnel to provide early assessments of in vivo target occupancy (TO) by ex vivo binding studies. Advanced compounds derived from iterative structure-activity relationship (SAR) studies possessed high potency in ex vivo binding studies and good brain penetration, promising preliminary in vivo efficacy, acceptable preclinical pharmacokinetics, and manageable DDI and bioactivation liabilities.

[Ind(2)TiMe(2)]: a general catalyst for the intermolecular hydroamination of alkynes.

[Ind(2)TiMe(2)] (Ind=indenyl) is a highly active and general catalyst for the intermolecular hydroamination of alkynes. It catalyzes the reaction of primary aryl-, tert-alkyl-, sec-alkyl-, and n-alkylamines with internal and terminal alkynes. In the case of unsymmetrically substituted 1-phenyl-2-alkylalkynes, the reactions occur with modest to excellent regioselectivities, whereby formation of the anti-Markovnikov regioisomers is favored. While the major product of hydroamination reactions of terminal arylalkynes is always the anti-Markovnikov isomer, alkylalkynes react with arylamines to preferably give the Markovnikov products. To achieve reasonable rates for the addition of sterically less hindered n-alkyl- and benzylamines to alkynes, these amines must be added slowly to the reaction mixtures. This behavior is explained by the fact that the catalytic cycle proposed on the basis of an initial kinetic investigation includes the possibility that the rate of the reaction increases with decreasing concentration of the employed amine. Furthermore, no dimerization of the catalytically active imido complex is observed in the hydroamination of 1-phenylpropyne with 4-methylaniline in the presence of [Ind(2)TiMe(2)] as catalyst. In general, a combination of [Ind(2)TiMe(2)]-catalyzed hydroamination of alkynes with subsequent reduction leads to the formation of secondary amines with good to excellent yields. Particularly impressive is that [Ind(2)TiMe(2)] makes it possible for the first time to perform the reactions of n-alkyl- and benzylamines with 1-phenylpropyne in a highly regioselective fashion.

The catalytic hydroamination of alkynes.

The direct addition of ammonia or primary and secondary amines to non-activated alkenes and alkynes is potentially the most efficient approach towards the synthesis of higher substituted nitrogen-containing products. It represents the most atom economic process for the formation of amines, enamines and imines, which are important bulk and fine chemicals or building blocks in organic synthesis. While the hydroamination of alkenes is still limited to more or less activated alkenes, great progress has been achieved in the case of alkynes over the last three years. To illustrate this progress, the review will mostly focus on recent developments in the field of intermolecular hydroamination of alkynes. However, if it is necessary for the discussion, older results and intramolecular reactions, which can be achieved more easily, will be mentioned as well.

The Mechanism of the [Cp2 TiMe2 ]-Catalyzed Intermolecular Hydroamination of Alkynes.

A complex interplay between the catalyst concentration and the reaction rate exists, as shown by kinetic studies, for the [Cp2 TiMe2 ]-catalyzed intermolecular hydroamination of alkynes. The reason for this is a reversible dimerization of the catalytically active species [Eq. (1)]. L1 , L2 =Cp (cyclopentadienyl), Tol-NH (Tol=4-MeC6 H4 , tolyl).