Centrally active and orally bioavailable antidotes for organophosphate exposure and methods for making and using them

US10913726B2 · kind B2 · utility

Assignees

• The Regents of the University of California · US
• THE SCRIPPS RESEARCH INSTITUTE · US

Inventors

• Palmer Taylor · Village of La Jolla, US
• Zoran Radic · San Diego, US
• Karl B. Sharpless · Brookline, US
• Valery Fokin · Oceanside, US
• Rakesh SIT · Village of La Jolla, US

Key dates

• Filing date: Jul 6, 2018
• Grant date: Feb 9, 2021
• Expiry date: Jul 6, 2038

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C07D487/08
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

In alternative embodiments, the invention provides nucleophilic hydroxyimino-acetamido alkylamine antidotes that cross the blood-brain barrier (BBB) to catalyze the hydrolysis of organophosphate (OP)-inhibited human acetylcholinesterase (hAChE) in the central nerve system (CNS). The hydroxyimino-acetamido alkylamines of the invention are designed to fit within AChE active center gorge dimensions, bind with reasonable affinity, and react with the conjugated phosphate atom in the gorge. The hydroxyimino-acetamido alkylamines of the invention are also designed to possess ionization states that govern affinity and reactivity for the two linked hAChE re-activation steps. In alternative embodiments, the invention provides pumps, devices, subcutaneous infusion devices, continuous subcutaneous infusion devices, infusion pens, needles, reservoirs, ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi-chambered pump, a syringe, a cartridge or a pen or a jet injector, comprising a compound of the invention.