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

Michael A Brodney; Gabriela Barreiro; Kevin Ogilvie; Eva Hajos-Korcsok; John Murray; Felix Vajdos; Claude Ambroise; Curt Christoffersen; Katherine Fisher; Lorraine Lanyon; JianHua Liu; Charles E Nolan; Jane M Withka; Kris A Borzilleri; Ivan Efremov; Christine E Oborski; Alison Varghese; Brian T O’Neill

doi:10.1021/jm3009426

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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

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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

Michael A Brodney, Gabriela Barreiro, Kevin Ogilvie, Eva Hajos-Korcsok, John Murray, Felix Vajdos, Claude Ambroise, Curt Christoffersen, Katherine Fisher, Lorraine Lanyon, …

Journal of medicinal chemistry, Vol.55(21), pp.9224-9239

11/08/2012

DOI: 10.1021/jm3009426

PMID: 22984865

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https://doi.org/10.7270/q22f7pk8View

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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.

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Title: Subtitle: 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
Creators: Michael A Brodney - Department of Neuroscience and ‡Center of Chemistry Innovation and Excellence, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
Gabriela Barreiro - Department of Neuroscience and ‡Center of Chemistry Innovation and Excellence, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
Kevin Ogilvie - Department of Neuroscience and ‡Center of Chemistry Innovation and Excellence, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
Eva Hajos-Korcsok - Department of Neuroscience and ‡Center of Chemistry Innovation and Excellence, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
John Murray - Department of Neuroscience and ‡Center of Chemistry Innovation and Excellence, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
Felix Vajdos - Department of Neuroscience and ‡Center of Chemistry Innovation and Excellence, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
Claude Ambroise - Department of Neuroscience and ‡Center of Chemistry Innovation and Excellence, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
Curt Christoffersen - Department of Neuroscience and ‡Center of Chemistry Innovation and Excellence, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
Katherine Fisher - Department of Neuroscience and ‡Center of Chemistry Innovation and Excellence, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
Lorraine Lanyon - Department of Neuroscience and ‡Center of Chemistry Innovation and Excellence, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
JianHua Liu - Department of Neuroscience and ‡Center of Chemistry Innovation and Excellence, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
Charles E Nolan - Department of Neuroscience and ‡Center of Chemistry Innovation and Excellence, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
Jane M Withka - Department of Neuroscience and ‡Center of Chemistry Innovation and Excellence, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
Kris A Borzilleri - Department of Neuroscience and ‡Center of Chemistry Innovation and Excellence, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
Ivan Efremov - Department of Neuroscience and ‡Center of Chemistry Innovation and Excellence, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
Christine E Oborski - Department of Neuroscience and ‡Center of Chemistry Innovation and Excellence, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
Alison Varghese - Department of Neuroscience and ‡Center of Chemistry Innovation and Excellence, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
Brian T O’Neill - Department of Neuroscience and ‡Center of Chemistry Innovation and Excellence, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
Resource Type: Journal article
Publication Details: Journal of medicinal chemistry, Vol.55(21), pp.9224-9239
DOI: 10.1021/jm3009426
PMID: 22984865
NLM abbreviation: J Med Chem
ISSN: 0022-2623
eISSN: 1520-4804
Language: English
Date published: 11/08/2012
Academic Unit: Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984094341402771

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