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

Brodney, Michael A.; Barreiro, Gabriela; Ogilvie, Kevin; Hajós‐Korcsok, Éva; Murray, John C.; Vajdos, F.F.; Ambroise, Claude; Christoffersen, Curt; Fisher, Katherine; Lanyon, Lorraine F.; Liu, Jianhua; Nolan, Charles E.; Withka, Jane M.; Borzilleri, Kris A.; Efremov, Ivan; Oborski, Christine; Varghese, Alison H.; O’Neill, Brian T.

doi:10.1021/jm3009426

Cited by 58 publications

(49 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…334 Spirocyclic sulfonamide 171 showed a BACE1 IC 50 of 20.9 μM. 335 Substituted aryl derivative 172 showed improvement in potency to 100 nM. The ortho-alkoxy substitution on the phenolic moiety is thought to have intramolecular hydrogen bonds that interfere with Pgp efflux recognition.…”

Section: Nonpeptide Inhibitorsmentioning

confidence: 99%

BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease

2014

View full text Add to dashboard Cite

BACE1 (β-secretase, memapsin 2, Asp2) has emerged as a promising target for the treatment of Alzheimer's Disease. BACE1 is an aspartic protease which functions in the first step of the pathway leading to the production and deposition of amyloid-β peptide (Aβ). Its gene deletion showed only mild phenotypes. BACE1 inhibition has direct implications in the Alzheimer's Disease pathology without largely affecting viability. However, inhibiting BACE1 selectively in vivo has presented many challenges to medicinal chemists. Since its identification in 2000, inhibitors covering many different structural classes have been designed and developed. These inhibitors can be largely classified as either peptidomimetic or non-peptidic inhibitors. Progress in these fields resulted in inhibitors that contain many targeted drug-like characteristics. In this review, we describe structure-based design strategies and evolution of a wide range of BACE1 inhibitors including compounds that have been shown to reduce brain Aβ, rescue the cognitive decline in transgenic AD mice and inhibitor drug candidates that are currently in clinical trials.

show abstract

Section: Nonpeptide Inhibitorsmentioning

confidence: 99%

BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease

2014

View full text Add to dashboard Cite

show abstract

“…WaterMap based predictions have supported the rational design of enzyme inhibitors in recent publications. 27 Initially, we investigated whether the WaterMap model generated for 8 crystal structure (Figure 2c) could explain binding affinity differences between benzamidine, 2, and 8. From Figure 2c, we can see that 4−5 unstable water sites (ΔG > 2 kcal/mol) are mapped collectively in the vicinity of 3 regions, (i) ether linker to the P1 benzamidine, (ii) pyridyl moiety, and (iii) P3/P4 benzamidine, suggesting that appending the pyridinyl bis-oxy-benzamidine to P1 benzamidine is likely to displace unstable water molecules resulting in free energy gain.…”

mentioning

confidence: 99%

Discovery of Pyridyl Bis(oxy)dibenzimidamide Derivatives as Selective Matriptase Inhibitors

Goswami

Mukherjee

Wohlfahrt

et al. 2013

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

Matriptase belongs to trypsin-like serine proteases involved in matrix remodeling/degradation, growth regulation, survival, motility, and cell morphogenesis. Herein, we report a structure-based approach, which led to the discovery of sulfonamide and amide derivatives of pyridyl bis(oxy)-benzamidine as potent and selective matriptase inhibitors. Co-crystal structures of selected compounds in complex with matriptase supported compound designing. Additionally, WaterMap analyses indicated the possibility of occupying a distinct pocket within the catalytic domain, exploration of which resulted in >100-fold improvement in potency. Co-crystal structure of 10 with matriptase revealed critical interactions leading to potent target inhibition and selectivity against other serine proteases.

show abstract

“…It is also important that drugs for AD treatment optimize CNS penetration by minimizing hydrogen bond donors and reducing P-gpmediated efflux [28][29][30]. The increase of P-gp expression and activity by a P-gp inducer could be an effective pharmacological strategy in slowing or halting the progression of AD [31].…”

Section: Journal Ofmentioning

confidence: 99%