1333227-01-2

Upstream product

• 1490613-08-5 C₁₃H₁₅NO₃ 
• 32946-56-8 N(τ)-(triphenylmethyl)-L-histidine methyl ester hydrochloride 
• 300804-20-0 [carboxymethyl-(3-phenyl-propyl)-amino]-acetic acid 
• 637-59-2 1-Bromo-3-phenylpropane 

Downstream Products

• 1333228-07-1 [{[(S)-1-Methylcarbamoyl-2-(1-trityl-1H-imidazol-4-yl)-ethylcarbamoyl]-methyl}-(3-phenyl-propyl)-amino]-acetic acid 
• 1333227-39-6 ({[(S)-2-(1H-Imidazol-4-yl)-1-methylcarbamoyl-ethylcarbamoyl]-methyl}-naphthalen-2-ylmethyl-amino)-acetic acid 
• 1333227-44-3 (S)-2-{2-[carboxymethyl-(3-phenyl-propyl)-amino]-acetylamino}-3-(1H-imidazol-4-yl)-propionic acid methyl ester. 
• 1333227-66-9 ((((S)-2-(1H-imidazol-4-yl)-1-methylcarbamoyl-ethylcarbamoyl)-methyl)-(3-phenyl-propyl)-amino)-acetic acid 

Relevant academic research and scientific papers

Structure-activity relationships of imidazole-derived 2-[ N-carbamoylmethyl-alkylamino]acetic acids, dual binders of human insulin-degrading enzyme

Insulin degrading enzyme (IDE) is a zinc metalloprotease that degrades small amyloid peptides such as amyloid-a and insulin. So far the dearth of IDE-specific pharmacological inhibitors impacts the understanding of its role in the physiopathology of Alzheimer's disease, amyloid-a clearance, and its validation as a potential therapeutic target. Hit 1 was previously discovered by high-throughput screening. Here we describe the structure-activity study, that required the synthesis of 48 analogues. We found that while the carboxylic acid, the imidazole and the tertiary amine were critical for activity, the methyl ester was successfully optimized to an amide or a 1,2,4-oxadiazole. Along with improving their activity, compounds were optimized for solubility, lipophilicity and stability in plasma and microsomes. The docking or co-crystallization of some compounds at the exosite or the catalytic site of IDE provided the structural basis for IDE inhibition. The pharmacokinetic properties of best compounds 44 and 46 were measured in vivo. As a result, 44 (BDM43079) and its methyl ester precursor 48 (BDM43124) are useful chemical probes for the exploration of IDE's role.

Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-β hydrolysis

Insulin degrading enzyme (IDE) is a highly conserved zinc metalloprotease that is involved in the clearance of various physiologically peptides like amyloid-beta and insulin. This enzyme has been involved in the physiopathology of diabetes and Alzheimer's disease. We describe here a series of small molecules discovered by screening. Co-crystallization of the compounds with IDE revealed a binding both at the permanent exosite and at the discontinuous, conformational catalytic site. Preliminary structure-activity relationships are described. Selective inhibition of amyloid-beta degradation over insulin hydrolysis was possible. Neuroblastoma cells treated with the optimized compound display a dose-dependent increase in amyloid-beta levels.