KMI-008, a novel β-Secretase inhibitor containing a hydroxymethylcarbonyl isostere as a transition-State mimic: design and synthesis of substrate-based octapeptides

Daisuke Shuto,Soko Kasai,Tooru Kimura,Ping Liu,Koushi Hidaka,Takashi Hamada,Saeko Shibakawa,Yoshio Hayashi,Chinatsu Hattori,Beata Szabo,Shoichi Ishiura,Yoshiaki Kiso

doi:10.1016/j.bmcl.2003.09.053

KMI-008, a novel β-Secretase inhibitor containing a hydroxymethylcarbonyl isostere as a transition-State mimic: design and synthesis of substrate-based octapeptides

Daisuke Shuto, Soko Kasai + Show 10 more

https://doi.org/10.1016/j.bmcl.2003.09.053

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Journal: Bioorganic & Medicinal Chemistry Letters	Publication Date: Nov 6, 2003
Citations: 88

Affiliation: Kyoto Pharmaceutical University, Tokyo University of Science

#Hydroxymethylcarbonyl Isostere #Β-secretase Inhibitors #Transition-state Mimic #Hydroxymethylcarbonyl #P1 Position #Structure–activity Relationships #BACE1 Inhibitors #Activity Relationships

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A novel class of substrate-based β-secretase (BACE1) inhibitors containing a hydroxymethylcarbonyl (HMC) isostere was designed and synthesized. Phenylnorstatine [(2R,3S)-3-amino-2-hydroxy-4-phenylbutyric acid; Pns] was an effective transition-state mimic at the P1 position. Structure–activity relationships (SARs) of the P3–P3′ positions of BACE1 inhibitors were studied.

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KMI-008, a novel β-Secretase inhibitor containing a hydroxymethylcarbonyl isostere as a transition-State mimic: design and synthesis of substrate-based octapeptides