title: Spirocyclic sulfamides as β-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.
abstract: β-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 Aβ(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 Aβ lowering versus that observed in wild-type (WT) mouse at an equivalent dose.
authors.affiliation: Department of Neuroscience, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States. michael.a.brodney@pfizer.com
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brodney
authors.forename: Gabriela
authors.initials: G
authors.lastname: Barreiro
authors.forename: Kevin
authors.initials: K
authors.lastname: Ogilvie
authors.forename: Eva
authors.initials: E
authors.lastname: Hajos-Korcsok
authors.forename: John
authors.initials: J
authors.lastname: Murray
authors.forename: Felix
authors.initials: F
authors.lastname: Vajdos
authors.forename: Claude
authors.initials: C
authors.lastname: Ambroise
authors.forename: Curt
authors.initials: C
authors.lastname: Christoffersen
authors.forename: Katherine
authors.initials: K
authors.lastname: Fisher
authors.forename: Lorraine
authors.initials: L
authors.lastname: Lanyon
authors.forename: Jianhua
authors.initials: J
authors.lastname: Liu
authors.forename: Charles E
authors.initials: CE
authors.lastname: Nolan
authors.forename: Jane M
authors.initials: JM
authors.lastname: Withka
authors.forename: Kris A
authors.initials: KA
authors.lastname: Borzilleri
authors.forename: Ivan
authors.initials: I
authors.lastname: Efremov
authors.forename: Christine E
authors.initials: CE
authors.lastname: Oborski
authors.forename: Alison
authors.initials: A
authors.lastname: Varghese
authors.forename: Brian T
authors.initials: BT
authors.lastname: O'Neill
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D005260:Female; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010539:Permeability; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014162:Transfection
chemical_list: C578485:4-(((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; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D001372:Aza Compounds; D013141:Spiro Compounds; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human