ABSTRACT
Chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase) are the enzymatically active chitinases that have been implicated in the pathology of chronic lung diseases such as asthma and interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis. The clinical and preclinical data suggest that pharmacological inhibition of CHIT1 might represent a novel therapeutic approach in IPF. Structural modification of an advanced lead molecule 3 led to the identification of compound 9 (OATD-01), a highly active CHIT1 inhibitor with both an excellent PK profile in multiple species and selectivity against a panel of other off-targets. OATD-01 given orally once daily in a range of doses between 30 and 100 mg/kg showed significant antifibrotic efficacy in an animal model of bleomycin-induced pulmonary fibrosis. OATD-01 is the first-in-class CHIT1 inhibitor, currently completed phase 1b of clinical trials, to be a potential treatment for IPF.
Subject(s)
Chitinases/antagonists & inhibitors , Enzyme Inhibitors/therapeutic use , Idiopathic Pulmonary Fibrosis/drug therapy , Piperidines/chemistry , Administration, Oral , Animals , Binding Sites , Bleomycin/toxicity , Catalytic Domain , Chitinases/metabolism , Clinical Trials, Phase I as Topic , Disease Models, Animal , Dogs , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Female , Half-Life , Humans , Idiopathic Pulmonary Fibrosis/chemically induced , Idiopathic Pulmonary Fibrosis/pathology , Lung/metabolism , Mice , Molecular Docking Simulation , Piperidines/pharmacokinetics , Piperidines/therapeutic use , Rats , Structure-Activity RelationshipABSTRACT
Human acidic mammalian chitinase (hAMCase) is one of two true chitinases in humans, the function of which remains elusive. In addition to the defense against highly antigenic chitin and chitin-containing pathogens in the gastric and intestinal contents, AMCase has been implicated in asthma, allergic inflammation, and ocular pathologies. Potent and selective small-molecule inhibitors of this enzyme have not been identified to date. Here we describe structural modifications of compound OAT-177, a previously developed inhibitor of mouse AMCase, leading to OAT-1441, which displays high activity and selectivity toward hAMCase. Significantly reduced off-target activity toward the human ether-à-go-go-related gene (hERG) and a good pharmacokinetic profile make OAT-1441 a potential candidate for further preclinical development as well as a useful tool compound to study the physiological role of hAMCase.
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
Escin, a complex mixture of pentacyclic triterpene saponins obtained from horse chestnut seeds extract (HCSE; Aesculus hippocastanum L.), constitutes a traditional herbal active substance of preparations (drugs) used for a treatment of chronic venous insufficiency and capillary blood vessel leakage. A new approach to exploitation of pharmacological potential of this saponin complex has been recently proposed, in which the ß-escin mixture is perceived as a source of a hitherto unavailable raw material, pentacyclic triterpene aglycone-protoescigenin. Although many liquid chromatography methods are described in the literature for saponins determination, analysis of protoescigenin is barely mentioned. In this work, a new ultra-high performance liquid chromatography (UHPLC) method developed for protoescigenin quantification has been described. CAD (charged aerosol detection), as a relatively new detection method based on aerosol charging, has been applied in this method as an alternative to ultraviolet (UV) detection. The influence of individual parameters on CAD response and sensitivity was studied. The detection was performed using CAD and UV (200 nm) simultaneously and the results were compared with reference to linearity, accuracy, precision and limit of detection.
Subject(s)
Chromatography, High Pressure Liquid/methods , Escin/chemistry , Pentacyclic Triterpenes/isolation & purification , Aerosols , Aesculus/chemistry , Chromatography, High Pressure Liquid/instrumentation , Limit of Detection , Molecular Structure , Pentacyclic Triterpenes/chemistry , Reproducibility of Results , Spectrophotometry, UltravioletABSTRACT
New triazole linked conjugates were obtained from protoescigenin monopropargyl ethers and sugar azides, under Cu(II) salt promotion in good yield, without losing isopropylidene protection.
Subject(s)
Glycoconjugates/chemical synthesis , Pentacyclic Triterpenes/chemistry , Triazoles/chemical synthesis , Catalysis , Copper/chemistry , Cycloaddition Reaction , Glycoconjugates/chemistry , Molecular Structure , Triazoles/chemistryABSTRACT
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.
