123183-72-2

Upstream product

• 24424-99-5 di-tert-butyl dicarbonate 
• 111-33-1 1,3-bis(methylamino)propane 
• 98642-44-5 tert-butyl (3-hydroxypropyl)methylcarbamate 
• 74-89-5 methylamine 
• 273756-96-0 methanesulfonic acid 2-(tert-butoxycarbonyl-methyl-amino)propyl ester 
• 1111237-72-9 C₁₇H₂₈N₂O₂ 

Downstream Products

• 1236154-24-7 methyl 7-{2-[{3-[(tert-butoxycarbonyl)(methyl)amino]propyl}(methyl)amino]ethyl}-14-cyclohexyl-7-hydroxy-4-methyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate 
• 1426551-51-0 quinone-trimethyllock-C₃-diamine-Boc 
• 7226-23-5 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone 
• 1246248-08-7 1-(2-{[3-(1-{4-[{3-[(tert-butoxycarbonyl)(methyl)amino]propyl}(methyl)carbamoyl]phenyl}piperidin-4-yl)propanoyl](methyl)amino}ethyl)piperidin-4-yl biphenyl-2-ylcarbamate 
• 1246246-97-8 C₄₄H₆₁FN₆O₆ 
• 1246246-95-6 tert-butyl (3-{[(4-amino-2-fluorophenyl)carbonyl](methyl)amino}propyl)methylcarbamate 
• 1246246-96-7 1-{2-[{6-[(3-Fluoro-4-{methyl[3-(methylamino)propyl]carbamoyl}phenyl)amino]hexanoyl}(meth yl)amino]ethyl}piperidin-4-yl biphenyl-2-ylcarbamate 

Relevant academic research and scientific papers

A Bioreductive Prodrug of Cucurbitacin B Significantly Inhibits Tumor Growth in the 4T1 Xenograft Mice Model

Cucurbitacin B (CuB), a highly cytotoxic constituent of the Cucurbitaceae plant, was identified to exhibit potent inhibitory activity against human cancer cells as well as normal cells. This disadvantage hampers the possibility of developing this compound into an anticancer drug candidate. In this work, several bioreductive prodrugs of CuB were designed to reduce toxicity to normal cells while maintaining the cytotoxic effect to cancer cells. Embedded with a bioreductive delivery and cleavable system in cancer tissues, cucurbitacin B-based prodrugs 1, 2, and 3 were synthesized and evaluated by in vitro and in vivo experiments. Compared with the parent CuB, prodrug 1 was found to significantly reduce the toxicity down to 310-fold lower against noncancerous cells. LC-MS analyses show that prodrug 1 efficiently releases the parent compound in the reductase-overexpressed MCF-7 cells. In addition, prodrug 1 shows satisfactory and comparable effectiveness in controlling tumor growth as that by tamoxifen in the 4T1 xenograft mice model.

METHODS AND COMPOUNDS FOR THE TREATMENT OF GENETIC DISEASE

The present disclosure relates to compounds and methods for modulating the expression of dmpk, and treating diseases and conditions in which dmpk plays an active role. The compound can be a transcription modulator molecule having a first terminus, a second terminus, and oligomeric backbone, wherein: a) the first terminus comprises a DNA-binding moiety capable of noncovalently binding to a nucleotide repeat sequence CAG or CTG; b) the second terminus comprises a protein-binding moiety binding to a regulatory molecule that modulates an expression of a gene comprising the nucleotide repeat sequence CAG or CTG; and c) the oligomeric backbone comprising a linker between the first terminus and the second terminus.

Fast Cyclization of a Proline-Derived Self-Immolative Spacer Improves the Efficacy of Carbamate Prodrugs

Self-immolative (SI) spacers are sophisticated chemical constructs designed for molecular delivery or material degradation. We describe herein a (S)-2-(aminomethyl)pyrrolidine SI spacer that is able to release different types of anticancer drugs (possessing either a phenolic or secondary and tertiary hydroxyl groups) through a fast cyclization mechanism involving carbamate cleavage. The high efficiency of drug release obtained with this spacer was found to be beneficial for the in vitro cytotoxic activity of protease-sensitive prodrugs, compared with a commonly used spacer of the same class. These findings expand the repertoire of degradation machineries and are instrumental for the future development of highly efficient delivery platforms.

IRAK DEGRADERS AND USES THEREOF

The present invention provides compounds, compositions thereof, and methods of using the same.

From Cells to Mice to Target: Characterization of NEU-1053 (SB-443342) and Its Analogues for Treatment of Human African Trypanosomiasis

Human African trypanosomiasis is a neglected tropical disease that is lethal if left untreated. Existing therapeutics have limited efficacy and severe associated toxicities. 2-(2-(((3-((1H-Benzo[d]imidazol-2-yl)amino)propyl)amino)methyl)-4,6-dichloro-1H-indol-1-yl)ethan-1-ol (NEU-1053) has recently been identified from a high-throughput screen of >42,000 compounds as a highly potent and fast-acting trypanocidal agent capable of curing a bloodstream infection of Trypanosoma brucei in mice. We have designed a library of analogues to probe the structure-activity relationship and improve the predicted central nervous system (CNS) exposure of NEU-1053. We report the activity of these inhibitors of T. brucei, the efficacy of NEU-1053 in a murine CNS model of infection, and identification of the target of NEU-1053 via X-ray crystallography.

Evaluation of quinazoline analogues as glucocerebrosidase inhibitors with chaperone activity

Gaucher disease is a lysosomal storage disorder (LSD) caused by deficiency in the enzyme glucocerebrosidase (GC). Small molecule chaperones of protein folding and translocation have been proposed as a promising therapeutic approach to this LSD. Most small molecule chaperones described in the literature contain an iminosugar scaffold. Here we present the discovery and evaluation of a new series of GC inhibitors with a quinazoline core. We demonstrate that this series can improve the translocation of GC to the lysosome in patient-derived cells. To optimize this chemical series, systematic synthetic modifications were performed and the SAR was evaluated and compared using three different readouts of compound activity: enzymatic inhibition, enzyme thermostabilization, and lysosomal translocation of GC.

MACROCYCLIC AND 7-AMINOALKYL-SUBSTITUTED BENZOXAZOCINES FOR TREATMENT OF HEPATITIS C INFECTIONS

The present invention provides a compound of formula (I), wherein R1 is selected from hydrogen, hydroxyl, fluoro or a C1-4alkoxy group or R1 is linked to R3 to form a 4, 5 or 6-membered aliphatic ring optionally

PYRROLOPYRIMIDINES

The present invention relates to compounds or pharmaceutically-acceptable salts thereof, processes for preparing them, pharmaceutical compositions containing them and their use in therapy. The invention particularly relates to compounds that are polo-like kinase (PLKs) inhibitors useful for the treatment of disease states mediated by PLK, especially PLK4, in particular such compounds that are useful in the treatment of pathological processes which involve an aberrant cellular proliferation, such as tumour growth, rheumatoid arthritis, restenosis and atherosclerosis.

Synthesis and characterisation of polyamine-poly(ethylene glycol) constructs for DNA binding and gene delivery

Improved non-viral vector systems are needed for efficient delivery of DNA to target cell nuclei in gene therapy. A series of linear polyamine-poly(ethylene glycol) (PEG) constructs has been synthesised by reaction of appropriately Boc-protected thermine derivatives with ω-methoxyPEG oxiranylmethyl ethers. Constructs carrying 1-3 MeOPEG units and 0, 2 or 4 N-methyl groups have been prepared by this method. H2N(CH2)3NBoc(CH2)3NBoc(CH2)3NHBoc was prepared efficiently by mono-trifluoroacetylation of thermine, attachment of Boc and removal of the trifluoroacetyl group in one pot. A similar process gave H2N(CH2)3NBoc(CH2)3NBoc(CH2)3NH2. BocMeN(CH2)3NHMe was alkylated by 1,3-dibromopropane to give BocMeN(CH2)3NMe(CH2)3NMe(CH2)3NMeBoc. A cyanoethylation/reduction sequence extended H2N(CH2)3NBoc(CH2)3NBoc(CH2)3NH2 to give H2N(CH2)3NBoc(CH2)3NBoc(CH2)3NBoc(CH2)3NBoc(CH2)3NH2, which was converted to its mono- and di-MeOPEG550 derivatives. Deprotection gave the linear polyamine-MeOPEG constructs. A branched triamine-poly(ethylene glycol) construct was prepared by acylation of (BocHN(CH2)3)2N(CH2)3NH2 with ω-methoxyPEG 550 chloroformate, followed by deprotection. A cyanoethylation/reduction/protection sequence from (H2N(CH2)3)2N(CH2)3NHBoc gave a protected pentamine. Alkylation with Br(CH2)5CONH(CH2)2NHBoc, deprotection, acylation with MeOPEG chloroformate and deprotection gave a pentamine-MeOPEG construct in which the MeOPEG is attached through a linker to the central amine. The linear hexamine construct carrying MeOPEG550 at only one terminus was the most effective DNA-interactive member of the two series in an ethidium displacement assay and was effective in delivering a reporter gene to RIF-1 tumours. Copyright (C) 2000 Elsevier Science Ltd.

Substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors, their preparation and pharmaceutical compositions containing them

The invention relates to new substituted 1-phenyl-3-pyrazolecarboxamides having a great affinity for human neurotensin receptors, to a process for preparing them and to pharmaceutical compositions containing them as active principles. More particularly, this invention relates to the discovery that the affinity for neurotensin receptors, especially human neurotensin receptors, is increased by substituting the phenyl group of 1-phenyl-3-pyrazolecarboxamide compounds with particular groups.