- Design and Synthesis of Imidazo[1,2-a]pyridines with Carboxamide Group Substitution and In silico Evaluation of their Interaction with a LuxR-type Quorum Sensing Receptor
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Quorum sensing, an important process of bacterial communication, is involved in the development of complex behavior and expression of virulence factors that become important due to its key role in infection process. In this manuscript, docking studies wer
- Reynoso Lara, Juan Emmanuel,Salgado-Zamora, Héctor,Bazin, Marc-Antoine,Campos-Aldrete, María Elena,Marchand, Pascal
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- HETEROCYCLIC COMPOUNDS AS PRMT5 INHIBITORS
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The compounds of Formula I, Formula Ia, and Formula Ib are described herein along with their analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites, and prodrugs thereof. These compounds inhibit PRMT5 and are useful as therpeautic or ameliorating agent for diseases that are involved in cellular growth such as malignant tumors, schizophrenia, Alzheimer's disease, Parkinson's disease and the like.
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Paragraph 000183
(2019/06/11)
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- SUBSTITUTED OXOPYRIDINE DERIVATIVES
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The invention relates to substituted oxopyridine derivatives and to processes for their preparation, and also to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular cardiovascular disorders, preferably thrombotic or thromboembolic disorders, and oedemas, and also ophthalmic disorders.
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Paragraph 0500; 0501; 0502; 0503
(2016/10/11)
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- Design, synthesis, and evaluation of linker-duocarmycin payloads: Toward selection of HER2-targeting antibody-drug conjugate SYD985
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Antibody-drug conjugates (ADCs) that are currently on the market or in clinical trials are predominantly based on two drug classes: auristatins and maytansinoids. Both are tubulin binders and block the cell in its progression through mitosis. We set out to develop a new class of linker-drugs based on duocarmycins, potent DNA-alkylating agents that are composed of a DNA-alkylating and a DNA-binding moiety and that bind into the minor groove of DNA. Linker-drugs were evaluated as ADCs by conjugation to the anti-HER2 antibody trastuzumab via reduced interchain disulfides. Duocarmycin 3b, bearing an imidazo[1,2-a]pyridine-based DNA-binding unit, was selected as the drug moiety, notably because of its rapid degradation in plasma. The drug was incorporated into the linker-drugs in its inactive prodrug form, seco-duocarmycin 3a. Linker attachment to the hydroxyl group in the DNA-alkylating moiety was favored over linking to the DNA-binding moiety, as the first approach gave more consistent results for in vitro cytotoxicity and generated ADCs with excellent human plasma stability. Linker-drug 2 was eventually selected based on the properties of the corresponding trastuzumab conjugate, SYD983, which had an average drug-to-antibody ratio (DAR) of about 2. SYD983 showed subnanomolar potencies against multiple human cancer cell lines, was highly efficacious in a BT-474 xenograft model, and had a long half-life in cynomolgus monkeys, in line with high stability in monkey and human plasma. Studies comparing ADCs with a different average DAR showed that a higher average DAR leads to increased efficacy but also to somewhat less favorable physicochemical and toxicological properties. Fractionation of SYD983 with hydrophobic interaction chromatography resulted in SYD985, consisting of about 95% DAR2 and DAR4 species in an approximate 2:1 ratio and having an average DAR of about 2.8. SYD985 combines several favorable properties from the unfractionated ADCs with an improved homogeneity. It was selected for further development and recently entered clinical Phase I evaluation.
- Elgersma, Ronald C.,Coumans, Ruud G. E.,Huijbregts, Tijl,Menge, Wiro M. P. B.,Joosten, John A. F.,Spijker, Henri J.,De Groot, Franciscus M. H.,Van Der Lee, Miranda M. C.,Ubink, Ruud,Van Den Dobbelsteen, Diels J.,Egging, David F.,Dokter, Wim H. A.,Verheijden, Gijs F. M.,Lemmens, Jacques M.,Timmers, C. Marco,Beusker, Patrick H.
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p. 1813 - 1835
(2015/06/16)
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- IMPROVED PROCESS FOR MAKING DUOCARMYCIN PRODRUGS
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The present invention relates to a process comprising converting a compound of formula (I) into a compound of formula (II) by reaction with an organolithium reagent, which compound can be further converted into duocarmycin analogues consisting of a DNA- alkylating and a DNA-binding part, and still further into corresponding antibody-drug conjugates.
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Page/Page column 20; 21
(2015/12/24)
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- NOVEL CC-1065 ANALOGS AND THEIR CONJUGATES
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This invention relates to novel analogs of the DNA-alkylating agent CC-1065 and to their conjugates. Furthermore this invention concerns intermediates for the preparation of said agents and conjugates. The conjugates are designed to release their (multiple) payload after one or more activation steps and/or at a rate and time span controlled by the conjugate in order to selectively deliver and/or controllably release one or more of said DNA alkylating agents. The agents, conjugates, and intermediates can be used to treat an illness that is characterized by undesired (cell) proliferation. As an example, the agents and the conjugates of this invention may be used to treat a tumor.
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Page/Page column 152
(2010/06/17)
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- Discovery of imidazo[1,2-a]pyridines as potent MCH1R antagonists
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A series of imidazo[1,2-a]pyridine derivatives was identified and evaluated for MCH1R binding and antagonistic activity. Introduction of a methyl substituent at the 3-position of imidazo[1,2-a]pyridine provided compounds with a significant improvement in MCH1R affinity. Representative compounds in this series exhibited good potency and brain exposure in rats.
- Kishino, Hiroyuki,Moriya, Minoru,Sakuraba, Shunji,Sakamoto, Toshihiro,Takahashi, Hidekazu,Suzuki, Takao,Moriya, Ryuichi,Ito, Masahiko,Iwaasa, Hisashi,Takenaga, Norihiro,Ishihara, Akane,Kanatani, Akio,Sato, Nagaaki,Fukami, Takehiro
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scheme or table
p. 4589 - 4593
(2010/04/25)
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- GUT MICROSOMAL TRIGLYCERIDE TRANSPORT PROTEIN INHIBITORS
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Compounds represented by formula (I): are inhibitors of gut microsomal triglyceride transfer protein. Such compounds are useful in treating diseases or conditions such as diabetes and obesity, along with patients are risk for developing such diseases or conditions.
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Page/Page column 111
(2008/12/08)
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- COMPARED REACTIVITY OF 3-, 5-, 6-, AND 8-AMINOIMIDAZOPYRIDINES IN COMBES REACTION: ACCESS TO IMIDAZONAPHTHYRIDINES AND DIPYRIDOIMIDAZOLE
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The synthesis of imidazonaphthyridines and dipyridoimidazole by treatment of aminoimidazopyridines following the Combes procedure is described.
- Blache, Yves,Gueiffier, Alain,Chavignon, Olivier,Viols, Henry,Teulade, Jean Claude,Chapat, Jean Pierre
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p. 1527 - 1532
(2007/10/02)
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