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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
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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.
Journal of Medicinal Chemistry 09/2012; · 4.80 Impact Factor
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Ivan V Efremov,
Felix F Vajdos,
Kris A Borzilleri,
Steven Capetta,
Hou Chen,
Peter H Dorff,
Jason K Dutra,
Steven W Goldstein,
Mahmoud Mansour,
Alexander McColl,
Stephen Noell,
Christine E Oborski,
Thomas N O'Connell,
Theresa J O'Sullivan,
Jayvardhan Pandit,
Hong Wang,
Binqing Wei,
Jane M Withka
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ABSTRACT: The aspartyl protease β-secretase, or BACE, has been demonstrated to be a key factor in the proteolytic formation of Aβ-peptide, a major component of plaques in the brains of Alzheimer's disease (AD) patients, and inhibition of this enzyme has emerged as a major strategy for pharmacologic intervention in AD. An X-ray-based fragment screen of Pfizer's proprietary fragment collection has resulted in the identification of a novel BACE binder featuring spiropyrrolidine framework. Although exhibiting only weak inhibitory activity against the BACE enzyme, the small compound was verified by biophysical and NMR-based methods as a bona fide BACE inhibitor. Subsequent optimization of the lead compound, relying heavily on structure-based drug design and computational prediction of physiochemical properties, resulted in a nearly 1000-fold improvement in potency while maintaining ligand efficiency and properties predictive of good permeability and low P-gp liability.
Journal of Medicinal Chemistry 04/2012; · 4.80 Impact Factor
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Antonia F Stepan,
Chakrapani Subramanyam, Ivan V Efremov,
Jason K Dutra,
Theresa J O'Sullivan,
Kenneth J DiRico,
W Scott McDonald,
Annie Won,
Peter H Dorff,
Charles E Nolan, [......],
Steven H Capetta,
Michael E Green,
Kapil Karki,
Evelyn Sibley,
Kevin P Atchison,
Andrew J Hallgren,
Christine E Oborski,
Ashley E Robshaw,
Blossom Sneed,
Christopher J O'Donnell
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ABSTRACT: Replacement of the central, para-substituted fluorophenyl ring in the γ-secretase inhibitor 1 (BMS-708,163) with the bicyclo[1.1.1]pentane motif led to the discovery of compound 3, an equipotent enzyme inhibitor with significant improvements in passive permeability and aqueous solubility. The modified biopharmaceutical properties of 3 translated into excellent oral absorption characteristics (~4-fold ↑ C(max) and AUC values relative to 1) in a mouse model of γ-secretase inhibition. In addition, SAR studies into other fluorophenyl replacements indicate the intrinsic advantages of the bicyclo[1.1.1]pentane moiety over conventional phenyl ring replacements with respect to achieving an optimal balance of properties (e.g., γ-secretase inhibition, aqueous solubility/permeability, in vitro metabolic stability). Overall, this work enhances the scope of the [1.1.1]-bicycle beyond that of a mere "spacer" unit and presents a compelling case for its broader application as a phenyl group replacement in scenarios where the aromatic ring count impacts physicochemical parameters and overall drug-likeness.
Journal of Medicinal Chemistry 03/2012; 55(7):3414-24. · 4.80 Impact Factor
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Antonia F Stepan,
Kapil Karki,
W Scott McDonald,
Peter H Dorff,
Jason K Dutra,
Kenneth J Dirico,
Annie Won,
Chakrapani Subramanyam, Ivan V Efremov,
Christopher J O'Donnell, [......],
Ashley E Robshaw,
David Riddell,
Theresa J O'Sullivan,
Evelyn Sibley,
Steven Capetta,
Kevin Atchison,
Andrew J Hallgren,
Emily Miller,
Anthony Wood,
R Scott Obach
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ABSTRACT: A metabolism-based approach toward the optimization of a series of N-arylsulfonamide-based γ-secretase inhibitors is reported. The lead cyclohexyl analogue 6 suffered from extensive oxidation on the cycloalkyl motif by cytochrome P450 3A4, translating into poor human liver microsomal stability. Knowledge of the metabolic pathways of 6 triggered a structure-activity relationship study aimed at lowering lipophilicity through the introduction of polarity. This effort led to several tetrahydropyran and tetrahydrofuran analogues, wherein the 3- and 4-substituted variants exhibited greater microsomal stability relative to their 2-substituted counterparts. Further reduction in lipophilicity led to the potent γ-secretase inhibitor and 3-substituted oxetane 1 with a reduced propensity toward oxidative metabolism, relative to its 2-substituted isomer. The slower rates of metabolism with 3-substituted cyclic ethers most likely originate from reductions in lipophilicity and/or unfavorable CYP active site interactions with the heteroatom. Preliminary animal pharmacology studies with a representative oxetane indicate that the series is generally capable of lowering Aβ in vivo. As such, the study also illustrates the improvement in druglikeness of molecules through the use of the oxetane motif.
Journal of Medicinal Chemistry 11/2011; 54(22):7772-83. · 4.80 Impact Factor
