Synthesis and in vivo evaluation of non-hepatotoxic acetaminophen analogs

Abstract

Abstract-A series of acetaminophen (APAP) analogs, 2-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)-N-(4-hydroxyphenyl)alkanecarboxamides, bearing a heterocyclic moiety linked to the p-acylaminophenol fragment, were prepared in a general project to develop APAP analogs with modulated pharmacokinetic profiles. Unexpectedly, the products described maintained the in vivo analgesic profile, while the characteristic hepatotoxicity of APAP was consistently reduced. One of the products, 5a, was studied in vivo in comparison with APAP. Compound 5a displayed an analgesic efficacy comparable to that of APAP. A relatively high acute oral dose of 5a (6 mmol/kg) produced no measurable toxicity, whereas the equimolar dose of APAP increased transaminase activity, depleted hepatic and renal glutathione, and resulted in mortality. In human hepatocytes (HEPG-2) and in human primary cultures of normal liver cells, APAP, but not 5a, was associated with apoptotic cell death, Fas-ligand up-regulation, and CAR (constitutive androstane receptor) activation, contributing to a favorable safety profile of 5a as an orally delivered analgesic.

First Multigram Preparation of SCP-123, A Novel Water-Soluble Analgesic

“…Therefore the design of a multi-gram synthesis focused on the initial preparation of 3 , followed by the subsequent hydrolysis to afford either 4 or 5 . Two synthetic routes have been established for the preparation of gram quantities of 3 8–10. As illustrated in Scheme 1, the two routes primarily differ in the sequence in which the saccharin moiety is added to the acetyl unit.…”

Pro-Drugs for Indirect Cannabinoids as Therapeutic Agents

“…For instance, with the mechanism of action of paracetamol now understood to be in great part due to AM404, the challenge becomes one of producing a variant of paracetamol, or related compound, that may degrade to AM404 but without producing the hepatotoxic effects of of paracetamol metabolism due to the alkylating metabolite N-acetyl-p-benzo-quinone imine, ("NAPQI"). Recently, Vaccarine et al [47] synthesised a number of paracetamol analogues with reduced hepatoxicity but that retained analgesia. It will be interesting to find out if these compounds also produce physiological levels of AM404, and are therefore improved pro-drugs for indirect cannabimimesis.…”

Advances in the Chemistry of Saccharins: From Synthetic Novelties Towards Biologically Active Compounds

“…One of the analogues (71, n = 5) displayed good oral analgesic efficacy, being a more potent analgesic than paracetamol. It was also devoid of hepatotoxic effects, rendering it a potential analgesic for the treatment of various pain states in humans [64].…”