L‐Proline as the catalyst: The first direct asymmetric α‐amination of aldehydes using L‐proline as the catalyst is presented (see scheme; Pg=protecting group). This new reaction gives easy access to optically active α‐amino aldehydes, α‐amino alcohols, and α‐amino acids from simple and easily available starting materials and catalysts. The reactions proceed in high yields and excellent enantioselectivities with as little as 2 mol % of the catalyst.

The first direct catalytic asymmetric alpha-amination of ketones catalyzed by l-proline has been developed. The reactions proceed with various azodicarboxylates as the nitrogen source in high yields and excellent enantioselectivities (up to 99% ee). The scope and potential of the reaction are demonstrated by further transformation of the alpha-hydrazino ketones formed to both optically active syn and anti-alpha-amino alcohol derivatives.

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Structure-based design, synthesis and biological evaluation of a series of peptidomimetic β-secretase inhibitors incorporating hydroxyethylamine isosteres are described. We have identified inhibitor 24 which has shown exceedingly potent activity in memapsin 2 enzyme inhibitory (K i 1.8 nM) and cellular (IC 50 = 1 nM in Chinese hamster cells) assays. Inhibitor 24 has also shown very impressive in vivo properties (up to 65% reduction of plasma Aβ) in transgenic mice. The X-ray structure of protein-ligand complexes of memapsin 2 revealed critical interactions in the memapsin 2 active site. KeywordsAlzheimer; design; synthesis; inhibitor; memapsin 2; secretase Memapsin 2 (β-secretase, BACE 1) has become a major target for the development of inhibitor drugs for the treatment of Alzheimers's Disease (AD). 1 Memapsin 2 is the first protease that cleaves β-amyloid precursor protein (APP) in the pathway leading to the generation of amyloid-β peptide (Aβ) in the brain. 2,3 The excess level of Aβ results in the formation of amyloid plaques and neurofibrillary tangles. The neurotoxicity of Aβ ultimately leads to neuronal death, brain inflammation, dementia and AD. 4 Consequently, inhibition of memapsin 2 has emerged as an excellent therapeutic target for the intervention of AD. On the basis of initial kinetics and substrate specificity information, we designed a number of potent inhibitors incorporating a nonhydrolyzable Leu-Ala hydroxyethylene dipeptide isostere. 5, 6 One of the early key inhibitors was OM99-2 (1 , Figure 1). It has shown potent inhibitory activity (K i = 1.6 nM) for human memapsin 2. 6a An X-ray crystal structure of 1-bound memapsin 2 provided critical molecular insight and drug-design templates for the memapsin 2 active site. 7 Based upon the crystallographic information and preliminary structure-activity relationship studies, we then designed a number of highly potent and selective inhibitors. 8 Inhibitor 2 incorporating Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. methylsulfonyl alanine as the P 1 -ligand and oxazolylmethyl urethane as the P 3 -ligand exhibited excellent potency (K i = 0.12 nM against memapsin 2) and selectivity over BACE-2 (3800-fold) and cathepsin D (2500-fold). 8 However, its cellular inhibitory potency was in the low micromolar range (IC 50 of 1.4 μM) in Chinese hamster ovary cells. NIH Public AccessTo further improve inhibitor properties, we subsequently developed inhibitors incorporating substituted isophthalamides as P 2 -P 3 ligands in combination with the Leu-Ala hydroxyethylene dipeptide isostere. 9 As shown in Figure 1, inh...

Structure-based design and synthesis of a number of potent and selective memapsin 2 inhibitors are described. These inhibitors were designed based upon the X-ray structure of memapsin 2-bound inhibitor 3 that incorporates methylsulfonyl alanine as the P2-ligand and a substituted pyrazole as the P3-ligand. Of particular importance, we examined the ability of the substituted isophthalic acid amide derivative to mimic the key interactions in the S2-S3 regions of the enzyme active sites of 3-bound memapsin 2. We investigated various substituted phenylethyl, alpha-methylbenzyl, and oxazolylmethyl groups as the P3-ligands. A number of inhibitors exhibited very potent inhibitory activity against mempasin 2 and good selectivity against memapsin 1. Inhibitor 5d has shown low nanomolar enzyme inhibitory potency (Ki=1.1 nM) and very good cellular inhibitory activity (IC50=39 nM). Furthermore, in a preliminary study, inhibitor 5d has shown 30% reduction of Abeta40 production in transgenic mice after a single intraperitoneal administration (8 mg/kg). A protein-ligand X-ray crystal structure of 5d-bound memapsin 2 provided vital molecular insight that can serve as an important guide to further design of novel inhibitors.