ABSTRACT
N-Nitrosamines (also referred to as nitrosamines) are a class of substances, many of which are highly potent mutagenic agents which have been classified as probable human carcinogens. Nitrosamine impurities have been a concern within the pharmaceutical industry and by regulatory authorities worldwide since June 2018, when regulators were informed of the presence of N-nitrosodimethylamine (NDMA) in the angiotensin-II receptor blocker (ARB) medicine, valsartan. Since that time, regulatory authorities have collaborated to share information and knowledge on issues related to nitrosamines with a goal of promoting convergence on technical issues and reducing and mitigating patient exposure to harmful nitrosamine impurities in human drug products. This paper shares current scientific information from a quality perspective on risk factors and potential root causes for nitrosamine impurities, as well as recommendations for risk mitigation and control strategies.
Subject(s)
Nitrosamines , Humans , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors , Risk Factors , Pharmaceutical PreparationsABSTRACT
A DNA-encoded macrocyclic peptide library was designed and synthesized with 2.4 × 1012 members composed of 4-20 natural and non-natural amino acids. Affinity-based selection was performed against two therapeutic targets, VHL and RSV N protein. On the basis of selection data, some peptides were selected for resynthesis without a DNA tag, and their activity was confirmed.
Subject(s)
Peptide Library , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Viral Proteins/metabolism , Von Hippel-Lindau Tumor Suppressor Protein/metabolism , Amino Acids/chemistry , DNA/chemistry , Drug Evaluation, Preclinical/methods , Molecular Targeted Therapy , Peptides, Cyclic/genetics , Polymerase Chain Reaction , Respiratory Syncytial Viruses , Viral Proteins/antagonists & inhibitors , Viral Proteins/chemistry , Von Hippel-Lindau Tumor Suppressor Protein/chemistryABSTRACT
Reductive desulfurisation of dithiocarbamates is conveniently achieved using H(3)PO(2)-Et(3)N-ACCN in refluxing dioxane. Fused and spirocyclic ß-lactams, prepared through 4-exo trig carbamoyl radical cyclisation-dithiocarbamate group transfer reactions, are reduced without fragmentation of the strained 4-membered ring. Diethyl tetraacetyl-d-glucopyranosyl dithiocarbamate is selectively reduced with or without acyloxy group migration depending on reaction conditions and choice of reductant. Deuterium incorporation from D(3)PO(2)-Et(3)N is observed for a system involving a nucleophilic radical intermediate, but not in the case of the electrophilic radical obtained through acyloxy group migration on a glucose derivative.
Subject(s)
Thiocarbamates/chemistry , Cyclization , Free Radicals/chemistry , Molecular Structure , Oxidation-Reduction , Spiro Compounds/chemical synthesis , Tin/chemistry , beta-Lactams/chemical synthesisABSTRACT
[formula: see text] The enantioselective synthesis of (R)-salmeterol has been achieved by using a sequence of supported reagents and sequestering agents. The saligenin core was installed by a regiospecific alkylation and a chiral auxilliary approach was employed to introduce the desired stereochemistry via a diastereoselective reduction.
