Novel Orally Bioavailable γ-Secretase Inhibitors with Excellent in Vivo Activity

Keown, Linda E.; Collins, Ian; Cooper, Laura C.; Harrison, Timothy; Madin, Andrew; Mistry, Jayesh; Reilly, Michael; Shaimi, Mohamed; Welch, Christopher J.; Clarke, Earl E.; Lewis, Huw D.; Wrigley, Jonathan D.J.; Best, Jonathan D.; Murray, Fraser; Shearman, Mark S.

doi:10.1021/jm900056p

Cited by 24 publications

(11 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The APP selectivity of the sulfonamide core appears to be very sensitive to structural modifications. For example, potent and in vivo active (bicycle(4:2:1) nonane sulfamide GSI's [91,92], as well as 4-cyclohexyl sulfones [12,93] have been reported as equipotent on APP and Notch. Interestingly, despite equipotent inhibition of APP and Notch processing by gamma-secretase, sulfones are reported to be well tolerated at 3 mg/kg dose in a three- month treatment study in the Tg2576 mouse model [14], although higher doses were not reported.…”

Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease

et al. 2010

View full text Add to dashboard Cite

IntroductionInhibition of gamma-secretase presents a direct target for lowering Aβ production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy.MethodsIn vitro assays monitoring inhibitor potencies at APP γ-site cleavage (equivalent to Aβ40), and Notch ε-site cleavage, in conjunction with a single cell assay to simultaneously monitor selectivity for inhibition of Aβ production vs. Notch signaling were developed to discover APP selective gamma-secretase inhibitors. In vivo efficacy for acute reduction of brain Aβ was determined in the PDAPP transgene model of AD, as well as in wild-type FVB strain mice. In vivo selectivity was determined following seven days x twice per day (b.i.d.) treatment with 15 mg/kg/dose to 1,000 mg/kg/dose ELN475516, and monitoring brain Aβ reduction vs. Notch signaling endpoints in periphery.ResultsThe APP selective gamma-secretase inhibitors ELN318463 and ELN475516 reported here behave as classic gamma-secretase inhibitors, demonstrate 75- to 120-fold selectivity for inhibiting Aβ production compared with Notch signaling in cells, and displace an active site directed inhibitor at very high concentrations only in the presence of substrate. ELN318463 demonstrated discordant efficacy for reduction of brain Aβ in the PDAPP compared with wild-type FVB, not observed with ELN475516. Improved in vivo safety of ELN475516 was demonstrated in the 7d repeat dose study in wild-type mice, where a 33% reduction of brain Aβ was observed in mice terminated three hours post last dose at the lowest dose of inhibitor tested. No overt in-life or post-mortem indications of systemic toxicity, nor RNA and histological end-points indicative of toxicity attributable to inhibition of Notch signaling were observed at any dose tested.ConclusionsThe discordant in vivo activity of ELN318463 suggests that the potency of gamma-secretase inhibitors in AD transgenic mice should be corroborated in wild-type mice. The discovery of ELN475516 demonstrates that it is possible to develop APP selective gamma-secretase inhibitors with potential for treatment for AD.

show abstract

Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease

et al. 2010

View full text Add to dashboard Cite

show abstract

“…12) has excellent in vitro potency (0.06 nM), a good PK profile in three preclinical species, including 35-45% oral bioavailability, and lowered amyloid-b in APP-YAC mice for which oral administration afforded an ED 50 of 1 mg/kg. 37 Triperiden (Fig. 12) is an anti-influenza agent that is believed to inhibit viral infection through increase of the internal pH in the prelysosomal compartment.…”

Section: Miscellaneous Carbocyclic Bicyclo Systemsmentioning

confidence: 99%

New and unusual scaffolds in medicinal chemistry

2011

View full text Add to dashboard Cite

Contemporary medicinal chemistry faces diverse challenges from several directions, including the need for both potency and specificity of any therapeutic agent; the increasingly demanding requirements of low toxicity shown across all patients treated; and the need for novelty in intellectual property, given the extensive use of benzenoid and heteroaromatic ring systems in numerous patents. Increasingly, such challenges are being met by a shift to new and/or unusual ring systems (scaffolds) that lie outside the field of (hetero)aromatic systems. This critical review surveys a necessarily limited selection of currently atypical scaffolds, chiefly drawn from the literature of the last three years, that have found application in medicinal chemistry, some being present in agents with therapeutic potential while others are found in agents already in clinical use (163 references).

show abstract

“…4-Bromo-5-ethoxycarbonyl-1-methyl-2-(1-naphthyl)imidazole (17). A solution of n-BuLi in n-hexane (1.5 M, 1.1 equiv, 0.18 mL) was added dropwise to a solution of 4,5-dibromo-1-methyl-2-(1-naphthyl)imidazole (8e) (0.25 mmol, 92 mg) in anhydrous THF (0.5 M, 0.50 mL) under an argon atmosphere at −78 °C.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Facile Synthetic Method for Diverse Polyfunctionalized Imidazoles by Means of Pd-Catalyzed C–H Bond Arylation of N-Methyl-4,5-dibromoimidazole

2014

View full text Add to dashboard Cite

C–H bond-selective arylation reaction of 4,5-dibromoimidazole with aryl iodides, catalyzed by the palladium-1,10-phenanthroline complex [Pd(phen)2](PF6)2, has been developed. The process tolerates the presence of a variety of functional groups on the aryl halide substrates. The products formed in these reactions were transformed to a variety of polyfunctionalized imidazoles by taking advantage of selective reactions of remaining C–Br bonds.

show abstract

Novel Orally Bioavailable γ-Secretase Inhibitors with Excellent in Vivo Activity

Cited by 24 publications

References 12 publications

Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease

Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease

New and unusual scaffolds in medicinal chemistry

Facile Synthetic Method for Diverse Polyfunctionalized Imidazoles by Means of Pd-Catalyzed C–H Bond Arylation of N-Methyl-4,5-dibromoimidazole

Contact Info

Product

Resources

About