PMID- 22984865
OWN - NLM
STAT- MEDLINE
DCOM- 20130226
LR  - 20181202
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 55
IP  - 21
DP  - 2012 Nov 8
TI  - Spirocyclic sulfamides as beta-secretase 1 (BACE-1) inhibitors for the treatment of 
      Alzheimer's disease: utilization of structure based drug design, WaterMap, and 
      CNS penetration studies to identify centrally efficacious inhibitors.
PG  - 9224-39
LID - 10.1021/jm3009426 [doi]
AB  - beta-Secretase 1 (BACE-1) is an attractive therapeutic target for the treatment and 
      prevention of Alzheimer's disease (AD). Herein, we describe the discovery of a 
      novel class of BACE-1 inhibitors represented by sulfamide 14g, using a medicinal 
      chemistry strategy to optimize central nervous system (CNS) penetration by 
      minimizing hydrogen bond donors (HBDs) and reducing P-glycoprotein (P-gp) 
      mediated efflux. We have also taken advantage of the combination of structure 
      based drug design (SBDD) to guide the optimization of the sulfamide analogues and 
      the in silico tool WaterMap to explain the observed SAR. Compound 14g is a potent 
      inhibitor of BACE-1 with excellent permeability and a moderate P-gp liability. 
      Administration of 14g to mice produced a significant, dose-dependent reduction in 
      central Abeta(X-40) levels at a free drug exposure equivalent to the whole cell 
      IC(50) (100 nM). Furthermore, studies of the P-gp knockout mouse provided 
      evidence that efflux transporters affected the amount of Abeta lowering versus that 
      observed in wild-type (WT) mouse at an equivalent dose.
FAU - Brodney, Michael A
AU  - Brodney MA
AD  - Department of Neuroscience, Pfizer Worldwide Research and Development, Eastern 
      Point Road, Groton, Connecticut 06340, United States. 
      michael.a.brodney@pfizer.com
FAU - Barreiro, Gabriela
AU  - Barreiro G
FAU - Ogilvie, Kevin
AU  - Ogilvie K
FAU - Hajos-Korcsok, Eva
AU  - Hajos-Korcsok E
FAU - Murray, John
AU  - Murray J
FAU - Vajdos, Felix
AU  - Vajdos F
FAU - Ambroise, Claude
AU  - Ambroise C
FAU - Christoffersen, Curt
AU  - Christoffersen C
FAU - Fisher, Katherine
AU  - Fisher K
FAU - Lanyon, Lorraine
AU  - Lanyon L
FAU - Liu, Jianhua
AU  - Liu J
FAU - Nolan, Charles E
AU  - Nolan CE
FAU - Withka, Jane M
AU  - Withka JM
FAU - Borzilleri, Kris A
AU  - Borzilleri KA
FAU - Efremov, Ivan
AU  - Efremov I
FAU - Oborski, Christine E
AU  - Oborski CE
FAU - Varghese, Alison
AU  - Varghese A
FAU - O'Neill, Brian T
AU  - O'Neill BT
LA  - eng
SI  - PDB/4FM7
SI  - PDB/4FM8
PT  - Journal Article
DEP - 20121008
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 
      (4-(((5R,7S)-1-(3-fluorophenyl)-3,7-dimethyl-2,2-dioxido-2-thia-1,3,8-triazaspiro(4,5)dec-8-yl)methyl)-2-isopropoxyphenol)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Aza Compounds)
RN  - 0 (Spiro Compounds)
RN  - 0 (Sulfonamides)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
RN  - EC 3.4.23.- (Aspartic Acid Endopeptidases)
RN  - EC 3.4.23.46 (BACE1 protein, human)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
MH  - Alzheimer Disease/*drug therapy
MH  - Amyloid Precursor Protein Secretases/*antagonists & inhibitors/chemistry
MH  - Amyloid beta-Peptides/metabolism
MH  - Animals
MH  - Aspartic Acid Endopeptidases/*antagonists & inhibitors/chemistry
MH  - Aza Compounds/*chemical synthesis/pharmacokinetics/pharmacology
MH  - Brain/*metabolism
MH  - Crystallography, X-Ray
MH  - Dogs
MH  - Drug Design
MH  - Female
MH  - Humans
MH  - Madin Darby Canine Kidney Cells
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Microsomes, Liver/metabolism
MH  - Models, Molecular
MH  - Molecular Structure
MH  - Permeability
MH  - Spiro Compounds/*chemical synthesis/pharmacokinetics/pharmacology
MH  - Stereoisomerism
MH  - Structure-Activity Relationship
MH  - Sulfonamides/*chemical synthesis/pharmacokinetics/pharmacology
MH  - Transfection
EDAT- 2012/09/19 06:00
MHDA- 2013/02/27 06:00
CRDT- 2012/09/19 06:00
PHST- 2012/09/19 06:00 [entrez]
PHST- 2012/09/19 06:00 [pubmed]
PHST- 2013/02/27 06:00 [medline]
AID - 10.1021/jm3009426 [doi]
PST - ppublish
SO  - J Med Chem. 2012 Nov 8;55(21):9224-39. doi: 10.1021/jm3009426. Epub 2012 Oct 8.