|
rdf:type |
|
|
lifeskim:mentions |
umls-concept:C0014442,
umls-concept:C0024485,
umls-concept:C0181586,
umls-concept:C0185125,
umls-concept:C0205234,
umls-concept:C0205314,
umls-concept:C0206755,
umls-concept:C0220908,
umls-concept:C0243077,
umls-concept:C0598139,
umls-concept:C0679622,
umls-concept:C1364818,
umls-concept:C1527148,
umls-concept:C1533134,
umls-concept:C1707689
|
|
pubmed:issue |
3
|
|
pubmed:dateCreated |
2010-2-4
|
|
pubmed:abstractText |
Fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design were used to identify novel inhibitors for BACE-1. A rapid optimization of an initial NMR hit was achieved by a combination of NMR and a functional assay, resulting in the identification of an isothiourea hit with a K(d) of 15 microM for BACE-1. NMR data and the crystal structure revealed that this hit makes H-bond interactions with the two catalytic aspartates, occupies the nonprime side region of the active site of BACE-1, and extends toward the S3 subpocket (S3sp). A focused NMR-based search for heterocyclic isothiourea isosteres resulted in several distinct classes of BACE-1 active site directed compounds with improved chemical stability and physicochemical properties. The strategy for optimization of the 2-aminopyridine lead series to potent inhibitors of BACE-1 was demonstrated. The structure-based design of a cyclic acylguanidine lead series and its optimization into nanomolar BACE-1 inhibitors are the subject of the companion paper
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Feb
|
|
pubmed:issn |
1520-4804
|
|
pubmed:author |
pubmed-author:BeyerBrian MBM,
pubmed-author:CzarnieckiMichaelM,
pubmed-author:GreenleeWilliam JWJ,
pubmed-author:HunterJohn CJC,
pubmed-author:KennedyMatthew EME,
pubmed-author:MadisonVincent SVS,
pubmed-author:McKittrickBrian ABA,
pubmed-author:NechutaTerry LTL,
pubmed-author:ParkerEric MEM,
pubmed-author:SeniorMary MMM,
pubmed-author:SmithElizabeth MEM,
pubmed-author:StamfordAndrew WAW,
pubmed-author:StricklandCoreyC,
pubmed-author:VoigtJohannes HJH,
pubmed-author:WangYu-SenYS,
pubmed-author:WyssDaniel FDF
|
|
pubmed:issnType |
Electronic
|
|
pubmed:day |
11
|
|
pubmed:volume |
53
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
942-50
|
|
pubmed:meshHeading |
pubmed-meshheading:20043700-Aminopyridines,
pubmed-meshheading:20043700-Amyloid Precursor Protein Secretases,
pubmed-meshheading:20043700-Aspartic Acid Endopeptidases,
pubmed-meshheading:20043700-Crystallography, X-Ray,
pubmed-meshheading:20043700-Drug Design,
pubmed-meshheading:20043700-Enzyme Inhibitors,
pubmed-meshheading:20043700-Humans,
pubmed-meshheading:20043700-Magnetic Resonance Spectroscopy,
pubmed-meshheading:20043700-Models, Molecular,
pubmed-meshheading:20043700-Molecular Structure,
pubmed-meshheading:20043700-Small Molecule Libraries,
pubmed-meshheading:20043700-Spectrometry, Mass, Electrospray Ionization,
pubmed-meshheading:20043700-Structure-Activity Relationship
|
|
pubmed:year |
2010
|
|
pubmed:articleTitle |
Application of fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design to identify novel microM leads for the development of nM BACE-1 (beta-site APP cleaving enzyme 1) inhibitors.
|
|
pubmed:affiliation |
Schering-Plough Research Institute, 320 Bent Street, Cambridge, Massachusetts 02141, USA. allen.yu-sen.wang@spcorp.com
|
|
pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, Non-U.S. Gov't
|
