Structure-based design of highly selective β-secretase inhibitors: synthesis, biological evaluation, and protein-ligand X-ray crystal structure.

The structure-based design, synthesis, and X-ray structure of protein-ligand complexes of exceptionally potent and selective β-secretase inhibitors are described. The inhibitors are designed specifically to interact with S(1)' active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 5 has exhibited exceedingly potent inhibitory activity (K(i) = 17 pM) and high selectivity over BACE 2 (>7000-fold) and cathepsin D (>250000-fold). A protein-ligand crystal structure revealed important molecular insight into these selectivities. These interactions may serve as an important guide to design selectivity over the physiologically important aspartic acid proteases.

[1]  J. D. McGaugh,et al.  Intraneuronal Aβ Causes the Onset of Early Alzheimer’s Disease-Related Cognitive Deficits in Transgenic Mice , 2005, Neuron.

[2]  J. Stables,et al.  Synthesis and anticonvulsant activities of (R)-(O)-methylserine derivatives , 1998 .

[3]  P. Stahl,et al.  Cathepsin D is membrane-associated in macrophage endosomes. , 1988, The Journal of biological chemistry.

[4]  C. Dingwall,et al.  Second generation of BACE-1 inhibitors part 3: Towards non hydroxyethylamine transition state mimetics. , 2009, Bioorganic & medicinal chemistry letters.

[5]  Arun K. Ghosh,et al.  The Discovery of β‐Secretase and Development toward a Clinical Inhibitor for AD: An Exciting Academic Collaboration , 2011 .

[6]  Arun K. Ghosh,et al.  In vivo inhibition of Aβ production by memapsin 2 (β‐secretase) inhibitors , 2004, Journal of neurochemistry.

[7]  L Hong,et al.  Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. , 2000, Science.

[8]  Nicolas Charrier,et al.  Synthesis of indoles : Efficient functionalisation of the 7-position , 2006 .

[9]  C. Peters,et al.  Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells. , 1995, The EMBO journal.

[10]  小池 正人.  Cathepsin D Deficiency Induces Lysosomal Storage with Ceroid Lipofuscin in Mouse CNS Neurons , 2002 .

[11]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[12]  J. Cumming,et al.  Peptidomimetic BACE1 Inhibitors for Treatment of Alzheimer's Disease: Design and Evolution , 2011 .

[13]  Arun K. Ghosh,et al.  Specificity of memapsin 1 and its implications on the design of memapsin 2 (beta-secretase) inhibitor selectivity. , 2002, Biochemistry.

[14]  Lin Hong,et al.  Design, synthesis, and X-ray structure of potent memapsin 2 (beta-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands. , 2007, Journal of medicinal chemistry.

[15]  M. Citron,et al.  Alzheimer's disease: strategies for disease modification , 2010, Nature Reviews Drug Discovery.

[16]  T. Poulos,et al.  Intramolecular hydrogen bonding: a potential strategy for more bioavailable inhibitors of neuronal nitric oxide synthase. , 2012, Bioorganic & medicinal chemistry.

[17]  M. Katharine Holloway,et al.  BACE-1 inhibition by a series of ψ[CH2NH] reduced amide isosteres , 2006 .

[18]  D. Holtzman,et al.  β‐Secretase inhibitor GRL‐8234 rescues age‐related cognitive decline in APP transgenic mice , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[19]  D. Selkoe,et al.  Alzheimer's disease: molecular understanding predicts amyloid-based therapeutics. , 2003, Annual review of pharmacology and toxicology.

[20]  J. Whisstock,et al.  Synthesis of new (-)-bestatin-based inhibitor libraries reveals a novel binding mode in the S1 pocket of the essential malaria M1 metalloaminopeptidase. , 2011, Journal of medicinal chemistry.

[21]  Lin Hong,et al.  Design, Synthesis and X-ray Structure of Protein−Ligand Complexes: Important Insight into Selectivity of Memapsin 2 (β-Secretase) Inhibitors , 2006 .

[22]  Heather B. Miller,et al.  Potent memapsin 2 (beta-secretase) inhibitors: design, synthesis, protein-ligand X-ray structure, and in vivo evaluation. , 2008, Bioorganic & medicinal chemistry letters.

[23]  Dongwoo Shin,et al.  Design of Potent Inhibitors for Human Brain Memapsin 2 (β-Secretase). , 2000, Journal of the American Chemical Society.

[24]  M. Goedert,et al.  A Century of Alzheimer's Disease , 2006, Science.

[25]  Arun K. Ghosh,et al.  Developing β‐secretase inhibitors for treatment of Alzheimer’s disease , 2012, Journal of neurochemistry.

[26]  Sahil Patel,et al.  Apo and Inhibitor Complex Structures of BACE (β-secretase) , 2004 .

[27]  Brian Clarke,et al.  Second generation of hydroxyethylamine BACE-1 inhibitors: optimizing potency and oral bioavailability. , 2008, Journal of medicinal chemistry.

[28]  B. Kuhn,et al.  Intramolecular hydrogen bonding in medicinal chemistry. , 2010, Journal of medicinal chemistry.

[29]  G. Koelsch,et al.  Proteolytic activation of recombinant pro-memapsin 2 (pro-beta-secretase) studied with new fluorogenic substrates. , 2000, Biochemistry.