Design and validation of bicyclic iminopyrimidinones as beta amyloid cleaving enzyme-1 (BACE1) inhibitors: conformational constraint to favor a bioactive conformation.

Mandal, Mihirbaran; Zhu, Zhaoning; Cumming, Jared N; Liu, Xiaoxiang; Strickland, Corey; Mazzola, Robert D; Caldwell, John P; Leach, Prescott; Grzelak, Michael; Hyde, Lynn; Zhang, Qi; Terracina, Giuseppe; Zhang, Lili; Chen, Xia; Kuvelkar, Reshma; Kennedy, Matthew E; Favreau, Leonard; Cox, Kathleen; Orth, Peter; Buevich, Alexei; Voigt, Johannes; Wang, Hongwu; Kazakevich, Irina; McKittrick, Brian A; Greenlee, William; Parker, Eric M; Stamford, Andrew W

Mandal, Mihirbaran; Zhu, Zhaoning; Cumming, Jared N; Liu, Xiaoxiang; Strickland, Corey; Mazzola, Robert D; Caldwell, John P; Leach, Prescott; Grzelak, Michael; Hyde, Lynn; Zhang, Qi; Terracina, Giuseppe; Zhang, Lili; Chen, Xia; Kuvelkar, Reshma; Kennedy, Matthew E; Favreau, Leonard; Cox, Kathleen; Orth, Peter; Buevich, Alexei; Voigt, Johannes; Wang, Hongwu; Kazakevich, Irina; McKittrick, Brian A; Greenlee, William; Parker, Eric M; Stamford, Andrew W.

Affiliation

Mandal M; Department of Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States. mihirbaran.mandal@merck.com

J Med Chem ; 55(21): 9331-45, 2012 Nov 08.

Article in En | MEDLINE | ID: mdl-22989333

Subject(s)

Amyloid Precursor Protein Secretases/antagonists & inhibitors; Aspartic Acid Endopeptidases/antagonists & inhibitors; Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis; Nitriles/chemical synthesis; Pyrimidines/chemical synthesis; Pyrimidinones/chemical synthesis; Thiophenes/chemical synthesis; Administration, Oral; Amyloid Precursor Protein Secretases/chemistry; Amyloid beta-Peptides/metabolism; Animals; Aspartic Acid Endopeptidases/chemistry; Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics; Bridged Bicyclo Compounds, Heterocyclic/pharmacology; Cerebral Cortex/metabolism; Crystallography, X-Ray; HEK293 Cells; Humans; Macaca fascicularis; Models, Molecular; Molecular Conformation; Nitriles/pharmacokinetics; Nitriles/pharmacology; Peptide Fragments/metabolism; Permeability; Pyrimidines/pharmacokinetics; Pyrimidines/pharmacology; Pyrimidinones/pharmacokinetics; Pyrimidinones/pharmacology; Quantum Theory; Rats; Stereoisomerism; Structure-Activity Relationship; Thermodynamics; Thiophenes/pharmacokinetics; Thiophenes/pharmacology

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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyrimidines / Pyrimidinones / Thiophenes / Aspartic Acid Endopeptidases / Bridged Bicyclo Compounds, Heterocyclic / Amyloid Precursor Protein Secretases / Nitriles Limits: Animals / Humans Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2012 Document type: Article Affiliation country: United States Country of publication: United States

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