104675-46-9Relevant academic research and scientific papers
A Non-Competitive Inhibitor of VCP/p97 and VPS4 Reveals Conserved Allosteric Circuits in Type I and II AAA ATPases
P?hler, Robert,Krahn, Jan H.,van den Boom, Johannes,Dobrynin, Grzegorz,Kaschani, Farnusch,Eggenweiler, Hans-Michael,Zenke, Frank T.,Kaiser, Markus,Meyer, Hemmo
, p. 1576 - 1580 (2018)
AAA ATPases have pivotal functions in diverse cellular processes essential for survival and proliferation. Revealing strategies for chemical inhibition of this class of enzymes is therefore of great interest for the development of novel chemotherapies or chemical tools. Here, we characterize the compound MSC1094308 as a reversible, allosteric inhibitor of the type II AAA ATPase human ubiquitin-directed unfoldase (VCP)/p97 and the type I AAA ATPase VPS4B. Subsequent proteomic, genetic and biochemical studies indicate that MSC1094308 binds to a previously characterized drugable hotspot of p97, thereby inhibiting the D2 ATPase activity. Our results furthermore indicate that a similar allosteric site exists in VPS4B, suggesting conserved allosteric circuits and drugable sites in both type I and II AAA ATPases. Our results may thus guide future chemical tool and drug discovery efforts for the biomedically relevant AAA ATPases.
Heterocyclization involving benzylic C(sp3)-H functionalization enabled by visible light photoredox catalysis
Pandey, Ganesh,Laha, Ramkrishna,Mondal, Pradip Kumar
supporting information, p. 9689 - 9692 (2019/08/15)
A general and efficient method for heterocyclization involving benzylic C(sp3)-H functionalization enabled by visible light photoredox catalysis to access a wide range of structurally diverse oxygen as well as nitrogen heterocycles up to a gram scale is reported. The potential application of this new methodology is demonstrated by the total synthesis of (-)-codonopsinine and (+)-centrolobine. Herein it is proposed that selectfluor, unlike a fluorinating reagent, acts as an oxidative quencher and a hydrogen radical acceptor.
Tricyclic compounds, their production and use
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, (2008/06/13)
A compound of the formula: wherein R1 is H or a substituent; m is 1-3; Ar is an aromatic group which may be substituted; X is a bond or a divalent straight-chain group having 1-6 atoms which may be substituted; Y is —S—, —O—, or —N(R2— (R2 is H or a substituent group), Z is —N= or —C(R3)= (R3 is H or a hydrocarbon group), ring A is a benzene ring; ring B is a 5- to 7-membered ring which may be substituted, or a salt thereof is useful for eliciting a prostaglandin I2 receptor agonistic effect.
CYCLIC ETHER COMPOUNDS AS SODIUM CHANNEL MODULATORS
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, (2008/06/13)
A compound of the formula: wherein R 1 and R 2 each represents hydrogen, lower alkyl which may be substituted or acyl; R 3, R 4 and R 5 each represents lower alkyl which may be substituted or lower alkoxy which may be substituted or R 4 and R 5 taken together represent a 5-or 6-membered carbocyclic group; R 6 represents lower alkyl; Ar represents an aromatic group which may be substituted; ring A represents a 5-to 8-membered nitrogen-containing heterocyclic ring which may be substituted; X represents lower alkylene which may be substituted; Y represents carbon or nitrogen; Za represents CH 2, COCH 2, OCH 2, SCH 2, NHCH 2, etc.; Zb represents a bond or a divalent aliphatic hydrocarbon group which may be substituted and may contain O, N or S; and m represents an integer of 1 to 3, or a salt thereof is useful for a pharmaceutical composition for modulating sodium channel.
Discovery of novel non-peptide CCR1 receptor antagonists
Ng, Howard P.,Karen, May,Bauman, John G.,Ghannam, Ameen,Islam, Imadul,Liang, Meina,Horuk, Richard,Hesselgesser, Joseph,Snider, R. Michael,Perez, H. Daniel,Morrissey, Michael M.
, p. 4680 - 4694 (2007/10/03)
Ligands for the CCR1 receptor (MIP-1α and RANTES) have been implicated in a number of chronic inflammatory diseases, most notably multiple sclerosis and rheumatoid arthritis. Because these ligands share a common receptor, CCR1, we sought to discover antagonists for this receptor as an approach to treating these disorders. A novel series of 4-hydroxypiperidines has been discovered by high throughput screening (HTS) which potently inhibits the binding of MIP-1α and RANTES to the recombinant human CCR1 chemokine receptor. The structure-activity relationships of various segments of this template are described as the initial HTS lead 1 was optimized synthetically to the highly potent receptor antagonist 6s. This compound has been shown to have at least 200-fold selectivity for inhibition of CCR1 over other human 7- TM receptors, including other chemokine receptors. In addition, data obtained from in vitro functional assays demonstrate the functional antagonism of compound 6s and structurally related analogues against the CCR1 receptor in a concentration dependent manner. The discovery and optimization of potent and selective CCR1 receptor antagonists represented by compound 6s potentially represent a novel approach to the treatment of chronic inflammatory diseases.
