Alzheimer's disease (AD) is characterized pathologically by the abundance of senile plaques and neurofibrillary tangles in the brain. We synthesized over 1200 novel gamma-secretase modulator (GSM) compounds that reduced A beta(42) levels without inhibiting epsilon-site cleavage of APP and Notch, the generation of the APP and Notch intracellular domains, respectively. These compounds also reduced A beta(40) levels while concomitantly elevating levels of A beta(38) and A beta(37). Immobilization of a potent GSM onto an agarose matrix quantitatively recovered Pen-2 and to a lesser degree PS-1 NTFs from cellular extracts. Moreover, oral administration (once daily) of another potent GSM to Tg 2576 transgenic AD mice displayed dose-responsive lowering of plasma and brain A beta(42); chronic daily administration led to significant reductions in both diffuse and neuritic plaques. These effects were observed in the absence of Notch-related changes (e.g., intestinal proliferation of goblet cells), which are commonly associated with repeated exposure to functional gamma-secretase inhibitors (GSIs).

The search for new active molecules with novel modes of action and desirable physical properties is an ongoing endeavour. This publication describes the follow-up chemistry of a biological hit discovered in the screening system of Novartis Crop Protection, the legacy agrochemical parent of Syngenta Crop Protection. This chemistry was optimized through classical synthetic methods and automated parallel synthesis with coverage of important physical properties such as lipophilicity or Clog P and solubility. Preliminary biological activity from the greenhouse and field data with symptomology is presented.

N',N'-Disubstituted homopiperazine derivatives have been discovered as CC-chemokine receptor 2b (CCR2b) inhibitors with submicromolar activity in the CCR2b binding assay. A 4-substituted benzyl group on one homopiperazine nitroger was an important moiety for binding affinity to the CCR2b receptor. The SAR for CCR2b binding affinity correlated inversely with the a factor of the functional group on this benzyl moiety. Introduction of hydroxy groups to appropriate positions in the 3,3-diphenylpropyl group on the other homopiperazine nitrogen increased CCR2b binding activity. The synthesis of an informer library to search for alternative substructures is also described. (C) 2004 Elsevier Ltd. All rights reserved.

Inhibition of the biosynthesis of proinflammatory cytokines such as tumor necrosis factor and interleukin-1 via p38 has been an approach toward the development of a disease modifying agent for the treatment of chronic inflammation and autoimmune diseases. The development of a new core structure of p38 inhibitors, 3-(4-fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b] pyridine, is described. X-ray crystallographic data of the lead bound to the active site of p38 was used to guide the optimization of the series. Specific focus was placed on modulating the physical properties of the core while maintaining potent inhibition of p38. These efforts identified 42c as a potent inhibitor of p38, which also possessed the required physical properties worthy of advanced studies.

A novel strategy for the synthesis of 3-sulfanylsubstituted 1-(arylamino)-pyrrolidine-2,5-dione derivatives via the alumina-catalyzed Michael addition of mercaptans to N-anilinomaleimides is described. The utilization of alumina in the synthesis offers important advantages such as good yields, convenience and mild conditions.

Liquid phase parallel synthesis has been developed to synthesize a novel series of iminodiacetic acid derivatives targeting the integrin receptors. This library was synthesized using a four-step reaction sequence. In each step of the sequence, the PEG-bound products were precipitated selectively and the excess reagents and the by-products were removed by simple filtration. The most notable result was that the library members were obtained in high purities (>95% pure).

A simple, versatile, and general approach to the solution phase, parallel synthesis of chemical libraries conducted on a generalized or universal template, which allows the preparation of multi-milligram quantities of each individual member, is described. In each step of the sequence, the reactants, unreacted starting material, reagents and their byproducts are removed by simple liquid/liquid or liquid/solid extractions providing the desired intermediates and final compounds in high purities (95% average) irrespective of the reaction yields and without deliberate reaction optimization.