Details

Autor(en) / Beteiligte

• COLE, Derek C
• STOCK, Joseph R
• GUIXIAN JIN
• LOHSE, Peter A
• MALAMAS, Michael S
• MANAS, Eric S
• MOORE, William J
• O'DONNELL, Mary-Margaret
• OLLAND, Andrea M
• ROBICHAUD, Albert J
• SVENSON, Kristine
• JUNJUN WU
• CHOPRA, Rajiv
• WAGNER, Eric
• BARD, Jonathan
• COWLING, Rebecca
• ELLINGBOE, John W
• FAN, Kristi Y
• HARRISON, Boyd L
• YUN HU
• JACOBSEN, Steve
• JENNINGS, Lee D

Titel

Acylguanidine inhibitors of β-secretase : Optimization of the pyrrole ring substituents extending into the S1 and S3 substrate binding pockets

Ist Teil von

• Bioorganic & medicinal chemistry letters, 2008-02, Vol.18 (3), p.1063-1066

Ort / Verlag

Oxford: Elsevier

Erscheinungsjahr

2008

Quelle

MEDLINE

Beschreibungen/Notizen

• Proteolytic cleavage of amyloid precursor protein by beta-secretase (BACE-1) and gamma-secretase leads to formation of beta-amyloid (A beta) a key component of amyloid plaques, which are considered the hallmark of Alzheimer's disease. Small molecule inhibitors of BACE-1 may reduce levels of A beta and thus have therapeutic potential for treating Alzheimer's disease. We recently reported the identification of a novel small molecule BACE-1 inhibitor N-[2-(2,5-diphenyl-pyrrol-1-yl)-acetyl]guanidine (3.a.1). We report here the initial hit-to-lead optimization of this hit and the SAR around the aryl groups occupying the S(1) and S(2') pockets leading to submicromolar BACE-1 inhibitors.