Highly Selective and Potent Human β-Secretase 2 (BACE2) Inhibitors against Type 2 Diabetes: Design, Synthesis, X-ray Structure and Structure-Activity Relationship Studies

Autor: Emma K. Lendy, Bhavanam Sekhara Reddy, Satish Kovela, Emilio L. Cárdenas, Andrew D. Mesecar, Yu-Chen Yen, Margherita Brindisi, Xiangping Huang, Jordan Tang, Arun K. Ghosh, Deborah Downs, Kalapala Venketeswara Rao
Přispěvatelé: Ghosh, A. K., Brindisi, M., Yen, Y. -C., Lendy, E. K., Kovela, S., Cardenas, E. L., Reddy, B. S., Rao, K. V., Downs, D., Huang, X., Tang, J., Mesecar, A. D.
Rok vydání: 2018
Předmět:
Isostere
Stereochemistry
BACE2 inhibitor
Drug Evaluation
Preclinical
Crystallography
X-Ray
Biochemistry
Article
chemistry.chemical_compound
Structure-Activity Relationship
Tmem27
Drug Discovery
Amyloid precursor protein
Ethylamines
Structure–activity relationship
Aspartic Acid Endopeptidases
Humans
Hypoglycemic Agents
General Pharmacology
Toxicology and Pharmaceutics
Enzyme Inhibitors
Pharmacology
chemistry.chemical_classification
type 2 diabete
Trifluoromethyl
Binding Sites
biology
Molecular Structure
Organic Chemistry
BACE2 inhibitors
structure-based design
type 2 diabetes
β-secretase 2
Molecular Docking Simulation
Memapsin 1
Enzyme
chemistry
Diabetes Mellitus
Type 2
Docking (molecular)
biology.protein
Molecular Medicine
Thermodynamics
Amyloid Precursor Protein Secretases
Selectivity
Protein Binding
Zdroj: ChemMedChem. 14(5)
ISSN: 1860-7187
Popis: Herein we present the design, synthesis, and biological evaluation of potent and highly selective β-secretase 2 (memapsin 1, beta-site amyloid precursor protein cleaving enzyme 2, or BACE 2) inhibitors. BACE2 has been recognized as an exciting new target for type 2 diabetes. The X-ray structure of BACE1 bound to inhibitor 2 a {N3 -[(1S,2R)-1-benzyl-2-hydroxy-3-[[(1S,2S)-2-hydroxy-1-(isobutylcarbamoyl)propyl]amino]propyl]-5-[methyl(methylsulfonyl)amino]-N1 -[(1R)-1-phenylpropyl]benzene-1,3-dicarboxamide} containing a hydroxyethylamine isostere was determined. Based on this structure, a computational docking study was performed which led to inhibitor 2 a-bound BACE2 models. These were used to optimize the potency and selectivity of inhibitors. A systematic structure-activity relationship study led to the identification of determinants of the inhibitors' potency and selectivity toward the BACE2 enzyme. Inhibitors 2 d [N3 -[(1S,2R)-1-benzyl-2-hydroxy-3-[[(1S,2S)-2-hydroxy-1-(isobutylcarbamoyl)pentyl]amino]propyl]-N1 -methyl-N1 -[(1R)-1-phenylpropyl]benzene-1,3-dicarboxamide; Ki =0.031 nm, selectivity over BACE1: ≈174 000-fold] and 3 l [N1 -((2S,3R)-3-hydroxy-1-phenyl-4-((3-(trifluoromethyl)benzyl)amino)butan-2-yl)-N3 ,5-dimethyl-N3 -((R)-1-phenylethyl)isophthalamide; Ki =1.6 nm, selectivity over BACE1: >500-fold] displayed outstanding potency and selectivity. Inhibitor 3 l is nonpeptide in nature and may pave the way to the development of a new class of potent and selective BACE2 inhibitors with clinical potential.
Databáze: OpenAIRE
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