111331-82-9Relevant articles and documents
Structural Optimization of 4-Chlorobenzoylpiperidine Derivatives for the Development of Potent, Reversible, and Selective Monoacylglycerol Lipase (MAGL) Inhibitors
Granchi, Carlotta,Rizzolio, Flavio,Palazzolo, Stefano,Carmignani, Sara,MacChia, Marco,Saccomanni, Giuseppe,Manera, Clementina,Martinelli, Adriano,Minutolo, Filippo,Tuccinardi, Tiziano
, p. 10299 - 10314 (2016)
Monoacylglycerol lipase (MAGL) inhibitors are considered potential therapeutic agents for a variety of pathological conditions, including several types of cancer. Many MAGL inhibitors are reported in literature; however, most of them showed an irreversible mechanism of action, which caused important side effects. The use of reversible MAGL inhibitors has been only partially investigated so far, mainly because of the lack of compounds with good MAGL reversible inhibition properties. In this study, starting from the (4-(4-chlorobenzoyl)piperidin-1-yl)(4-methoxyphenyl)methanone (CL6a) lead compound that showed a reversible mechanism of MAGL inhibition (Ki = 8.6 μM), we started its structural optimization and we developed a new potent and selective MAGL inhibitor (17b, Ki = 0.65 μM). Furthermore, modeling studies suggested that the binding interactions of this compound replace a structural water molecule reproducing its H-bonds in the MAGL binding site, thus identifying a new key anchoring point for the development of new MAGL inhibitors.
Molecular iodine-catalyzed facile procedure for N-Boc protection of amines
Varala, Ravi,Nuvula, Sreelatha,Adapa, Srinivas R.
, p. 8283 - 8286 (2006)
An efficient and practical protocol for the protection of various structurally and electronically divergent aryl and aliphatic amines using (Boc)2O in the presence of a catalytic amount of molecular iodine (10 mol%) under solvent-free conditions at ambient temperature is presented.
2-Arylamino-6-ethynylpurines are cysteine-targeting irreversible inhibitors of Nek2 kinase
Bayliss, Richard,Boxall, Kathy,Carbain, Benoit,Coxon, Christopher R.,Fry, Andrew M.,Golding, Bernard T.,Griffin, Roger J.,Hardcastle, Ian R.,Harnor, Suzannah J.,Mas-Droux, Corine,Matheson, Christopher J.,Newell, David R.,Richards, Mark W.,Sivaprakasam, Mangaleswaran,Turner, David,Cano, Céline
supporting information, p. 707 - 731 (2020/08/24)
Renewed interest in covalent inhibitors of enzymes implicated in disease states has afforded several agents targeted at protein kinases of relevance to cancers. We now report the design, synthesis and biological evaluation of 6-ethynylpurines that act as covalent inhibitors of Nek2 by capturing a cysteine residue (Cys22) close to the catalytic domain of this protein kinase. Examination of the crystal structure of the non-covalent inhibitor 3-((6-cyclohexylmethoxy-7H-purin-2-yl)amino)benzamide in complex with Nek2 indicated that replacing the alkoxy with an ethynyl group places the terminus of the alkyne close to Cys22 and in a position compatible with the stereoelectronic requirements of a Michael addition. A series of 6-ethynylpurines was prepared and a structure activity relationship (SAR) established for inhibition of Nek2. 6-Ethynyl-N-phenyl-7H-purin-2-amine [IC50 0.15 μM (Nek2)] and 4-((6-ethynyl-7H-purin-2-yl)amino)benzenesulfonamide (IC50 0.14 μM) were selected for determination of the mode of inhibition of Nek2, which was shown to be time-dependent, not reversed by addition of ATP and negated by site directed mutagenesis of Cys22 to alanine. Replacement of the ethynyl group by ethyl or cyano abrogated activity. Variation of substituents on the N-phenyl moiety for 6-ethynylpurines gave further SAR data for Nek2 inhibition. The data showed little correlation of activity with the nature of the substituent, indicating that after sufficient initial competitive binding to Nek2 subsequent covalent modification of Cys22 occurs in all cases. A typical activity profile was that for 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide [IC50 0.06 μM (Nek2); GI50 (SKBR3) 2.2 μM] which exhibited >5-10-fold selectivity for Nek2 over other kinases; it also showed > 50% growth inhibition at 10 μM concentration against selected breast and leukaemia cell lines. X-ray crystallographic analysis confirmed that binding of the compound to the Nek2 ATP-binding site resulted in covalent modification of Cys22. Further studies confirmed that 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide has the attributes of a drug-like compound with good aqueous solubility, no inhibition of hERG at 25 μM and a good stability profile in human liver microsomes. It is concluded that 6-ethynylpurines are promising agents for cancer treatment by virtue of their selective inhibition of Nek2. This journal is
AMINOPYRIDINE DERIVATIVES AS PHOSPHATIDYLINOSITOL PHOSPHATE KINASE INHIBITORS
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Paragraph 0634, (2019/07/13)
The invention relates to inhibitors of PI5P4K inhibitors useful in the treatment of cancers, neurodegenerative diseases, inflammatory disorders, and metabolic diseases, having the Formula: (I) where A, B, R1, X1, X2, and W are described herein.
Design and synthesis of selective CYP1B1 inhibitor via dearomatization of α-naphthoflavone
Kubo, Makoto,Yamamoto, Keiko,Itoh, Toshimasa
, p. 285 - 304 (2019/01/04)
Selective cytochrome P450 (CYP) 1B1 inhibition has potential as an anticancer strategy that is unrepresented in the current clinical arena. For development of a selective inhibitor, we focused on the complexity caused by sp3-hybridized carbons and synthesized a series of benzo[h]chromone derivatives linked to a non-aromatic B-ring using α-naphthoflavone (ANF) as the lead compound. Ring structure comparison suggested compound 37 as a suitable cyclohexyl-core with improved solubility. Structural evolution of 37 produced the azide-containing cis-49a, which had good properties in three important respects: (1) selectivity for CYP1B1 over CYP1A1 and CYP1A2 (120-times and 150-times, respectively), (2) greater inhibitory potency of >2 times that of ANF, and (3) improved solubility. The corresponding aromatic B-ring compound 59a showed low selectivity and poor solubility. To elucidate the binding mode, we performed X-ray crystal structure analysis, which revealed the interaction mode and explained the subtype selectivity of cis-49a.
Carboxylation of Aryl Triflates with CO2 Merging Palladium and Visible-Light-Photoredox Catalysts
Bhunia, Samir Kumar,Das, Pritha,Nandi, Shantanu,Jana, Ranjan
supporting information, p. 4632 - 4637 (2019/06/27)
We report herein a visible-light-promoted, highly practical carboxylation of readily accessible aryl triflates at ambient temperature and a balloon pressure of CO2 by the combined use of palladium and photoredox Ir(III) catalysts. Strikingly, the stoichiometric metallic reductant is replaced by a nonmetallic amine reductant providing an environmentally benign carboxylation process. In addition, one-pot synthesis of a carboxylic acid directly from phenol and modification of estrone and concise synthesis of pharmaceutical drugs adapalene and bexarotene have been accomplished via late-stage carboxylation reaction. Furthermore, a parallel decarboxylation-carboxylation reaction has been demonstrated in an H-type closed vessel that is an interesting concept for the strategic sector. Spectroscopic and spectroelectrochemical studies indicated electron transfer from the Ir(III)/DIPEA combination to generate aryl carboxylate and Pd(0) for catalytic turnover.
Comprehensive Synthesis of Amino Acid-Derived Thiazole Peptidomimetic Analogues to Understand the Enigmatic Drug/Substrate-Binding Site of P-Glycoprotein
Patel, Bhargav A.,Abel, Biebele,Barbuti, Anna Maria,Velagapudi, Uday Kiran,Chen, Zhe-Sheng,Ambudkar, Suresh V.,Talele, Tanaji T.
, p. 834 - 864 (2018/02/17)
A novel set of 64 analogues based on our lead compound 1 was designed and synthesized with an initial objective of understanding the structural requirements of ligands binding to a highly perplexing substrate-binding site of P-glycoprotein (P-gp) and their effect on modulating the ATPase function of the efflux pump. Compound 1, a stimulator of P-gp ATPase activity, was transformed to ATPase inhibitory compounds 39, 53, and 109. The ATPase inhibition by these compounds was predominantly contributed by the presence of a cyclohexyl group in lieu of the 2-aminobenzophenone moiety of 1. The 4,4-difluorocyclohexyl analogues, 53 and 109, inhibited the photolabeling by [125I]-IAAP, with IC50 values of 0.1 and 0.76 μM, respectively. Selected compounds were shown to reverse paclitaxel resistance in HEK293 cells overexpressing P-gp and were selective toward P-gp over CYP3A4. Induced-fit docking highlighted a plausible binding pattern of inhibitory compounds in the putative-binding pocket of P-gp. The current study underscores the stringent requirement by P-gp to bind to chemically similar molecules.
Carboxylation of Aromatic and Aliphatic Bromides and Triflates with CO2 by Dual Visible-Light–Nickel Catalysis
Meng, Qing-Yuan,Wang, Shun,K?nig, Burkhard
supporting information, p. 13426 - 13430 (2017/10/07)
We report the efficient carboxylation of bromides and triflates with K2CO3 as the source of CO2 in the presence of an organic photocatalyst in combination with a nickel complex under visible light irradiation at room temperature. The reaction is compatible with a variety of functional groups and has been successfully applied to the synthesis and derivatization of biologically active molecules. In particular, the carboxylation of unactivated cyclic alkyl bromides proceeded well with our protocol, thus extending the scope of this transformation. Spectroscopic and spectroelectrochemical investigations indicated the generation of a Ni0 species as a catalytic reactive intermediate.
KINASE INHIBITORS
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Paragraph 0129; 0130, (2017/10/07)
Compounds that inhibit kinase Lck or Btk, pharmaceutically acceptable salts, hydrides, stereoisomers and pharmaceutical compositions thereof are disclosed.
Structure-Based Discovery of Novel and Selective 5-Hydroxytryptamine 2B Receptor Antagonists for the Treatment of Irritable Bowel Syndrome
Zhou, Yu,Ma, Jing,Lin, Xingyu,Huang, Xi-Ping,Wu, Kaichun,Huang, Niu
, p. 707 - 720 (2016/02/09)
Here we employed structure-based ligand discovery techniques to explore a recently determined crystal structure of the 5-hydroxytryptamine 2B (5-HT2B) receptor. Ten compounds containing a novel chemical scaffold were identified; among them, seven molecules were active in cellular function assays with the most potent one exhibiting an IC50 value of 27.3 nM. We then systematically probed the binding characteristics of this scaffold by designing, synthesizing, and testing a series of structural modifications. The structure-activity relationship studies strongly support our predicted binding model. The binding profiling across a panel of 11 5-HT receptors indicated that these compounds are highly selective for the 5-HT2B receptor. Oral administration of compound 15 (30 mg/kg) produced significant attenuation of visceral hypersensitivity in a rat model of irritable bowel syndrome (IBS). We expect this novel scaffold will serve as the foundation for the development of 5-HT2B antagonists for the treatment of IBS.
