ABSTRACT
This article describes our work towards the identification of a potent and selective inhibitor of mouse chitotriosidase (mCHIT1). A series of small molecule inhibitors of mCHIT1 and mAMCase have been developed from early lead compound 1. Examination of synthetized analogues led to discovery of several novel highly potent compounds. Among them compound 9 (OAT-2068) displays a remarkable 143-fold mCHIT1 vs. mAMCase selectivity. To explain the observed SAR molecular docking experiments were performed, which were in line with the experimental data from the enzymatic assays. Inhibitor 9 (OAT-2068) was found to have an excellent pharmacokinetic profile. This, together with high activity and selectivity, makes the compound an ideal and unique tool for studying the role of CHIT1 in biological models.
Subject(s)
Drug Discovery , Hexosaminidases/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Administration, Oral , Animals , Biological Availability , Dose-Response Relationship, Drug , Hexosaminidases/metabolism , Mice , Molecular Docking Simulation , Molecular Structure , Small Molecule Libraries/administration & dosage , Small Molecule Libraries/chemistry , Structure-Activity RelationshipABSTRACT
A physicochemical characterization of the process-related impurities associated with the synthesis of pemetrexed disodium was performed. The possibility of pemetrexed impurities forming has been mentioned in literature, but no study on their structure has been published yet. This paper describes the development of the synthesis methods for these compounds and discusses their structure elucidation on the basis of two-dimensional NMR experiments and MS data. The identification of these impurities should be useful for the quality control during the production of the pemetrexed disodium salt.
Subject(s)
Antineoplastic Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Pemetrexed/chemical synthesis , Antineoplastic Agents/chemistry , Dipeptides/chemistry , Dipeptides/isolation & purification , Enzyme Inhibitors/chemistry , Formamides/chemistry , Formamides/isolation & purification , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Pemetrexed/chemistry , Quality Control , StereoisomerismABSTRACT
A two-step chemical process for controlled degradation of escin, affording a mixture of olean-12-ene sapogenins, was elaborated and scaled up. The main component of the mixture--protoescigenin--was isolated and purified, in the form of its corresponding monohydrate, without resource to chromatographic methods. This material was further converted into the high purity 3,24;16,22-di-O,O-isopropylidene derivative in a validated large scale laboratory process.
