Syntheses and spectral properties of β‐iodoureas and 2‐amino‐4,4‐diphenyl‐2‐oxazolines

Fernández, José Manuel Garcı́a; Mellet, Carmen Ortiz; Adrian, M.A. Pradera; Mota, J. Fuentes

doi:10.1002/jhet.5570280339

Cited by 3 publications

(3 citation statements)

References 12 publications

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“…Reaction of ketone 5 with MeMgCl and subsequent HCl treatment afforded an unstable exo -olefin. The olefin was treated directly with in situ generated iodine isocyanate followed by a solution of ammonia in 2-propanol to yield the 2-aminooxazoline xanthene in racemic form . Separation of the racemate through chiral supercritical fluid chromatography (SFC) afforded the ( S )-enantiomer 6 on multigram scale.…”

Section: Chemistrymentioning

confidence: 99%

Inhibitors of β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (S)-7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (AMG-8718)

et al. 2014

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We have previously shown that the aminooxazoline xanthene scaffold can generate potent and orally efficacious BACE1 inhibitors although certain of these compounds exhibited potential hERG liabilities. In this article, we describe 4-aza substitution on the xanthene core as a means to increase BACE1 potency while reducing hERG binding affinity. Further optimization of the P3 and P2' side chains resulted in the identification of 42 (AMG-8718), a compound with a balanced profile of BACE1 potency, hERG binding affinity, and Pgp recognition. This compound produced robust and sustained reductions of CSF and brain Aβ levels in a rat pharmacodynamic model and exhibited significantly reduced potential for QTc elongation in a cardiovascular safety model.

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Section: Chemistrymentioning

confidence: 99%

Inhibitors of β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (S)-7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (AMG-8718)

et al. 2014

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“…33 The addition of in situ generated iodine isocyanate to the olefin followed by treatment with ammonium hydroxide led to 2-aminooxazoline aryl bromide 21. 34 Suzuki coupling of aryl bromide 21 with a variety of arylboronic acids generated the desired 2-aminooxazoline xanthenes 9.…”

Section: ■ Chemistrymentioning

confidence: 99%

“…Subsequent Friedel–Crafts acylation provided xanthenone 19 which was converted to the terminal olefin 20 by a Peterson-type olefination . The addition of in situ generated iodine isocyanate to the olefin followed by treatment with ammonium hydroxide led to 2-aminooxazoline aryl bromide 21 . Suzuki coupling of aryl bromide 21 with a variety of arylboronic acids generated the desired 2-aminooxazoline xanthenes 9 .…”

Section: Chemistrymentioning

confidence: 99%

Structure- and Property-Based Design of Aminooxazoline Xanthenes as Selective, Orally Efficacious, and CNS Penetrable BACE Inhibitors for the Treatment of Alzheimer’s Disease

Huang

Cheng

et al. 2012

J. Med. Chem.

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A structure- and property-based drug design approach was employed to identify aminooxazoline xanthenes as potent and selective human β-secretase inhibitors. These compounds exhibited good isolated enzyme, cell potency, and selectivity against the structurally related aspartyl protease cathepsin D. Our efforts resulted in the identification of a potent, orally bioavailable CNS penetrant compound that exhibited in vivo efficacy. A single oral dose of compound 11a resulted in a significant reduction of CNS Aβ40 in naive rats.

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Lead Optimization and Modulation of hERG Activity in a Series of Aminooxazoline Xanthene β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors

et al. 2014

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The optimization of a series of aminooxazoline xanthene inhibitors of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Aβ lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust Aβ reduction in a rat pharmacodynamic model (78% Aβ reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.

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Syntheses and spectral properties of β‐iodoureas and 2‐amino‐4,4‐diphenyl‐2‐oxazolines

Cited by 3 publications

References 12 publications

Inhibitors of β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (S)-7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (AMG-8718)

Inhibitors of β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (S)-7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (AMG-8718)

Structure- and Property-Based Design of Aminooxazoline Xanthenes as Selective, Orally Efficacious, and CNS Penetrable BACE Inhibitors for the Treatment of Alzheimer’s Disease

Lead Optimization and Modulation of hERG Activity in a Series of Aminooxazoline Xanthene β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors

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