Tag: M.W=100-150

Shukla, Manojkumar R. published the artcileDiscovery of a Potent and Selective PI3Kδ Inhibitor (S)-2,4-Diamino-6-((1-(7-fluoro-1-(4-fluorophenyl)-4-oxo-3-phenyl-4H-quinolizin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile with Improved Pharmacokinetic Profile and Superior Efficacy in Hematological Cancer Models, Related Products of amides-buliding-blocks, the main research area is anticancer PI3K delta inhibitor DLBCL cell pharmacokinetic bioavailability iNHL.

PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a “”three-blade propeller”” shaped lead, 2,3-disubstituted quinolizinone 11, through a 1,2-disubstituted quinolizinone 20 to a novel “”four-blade propeller”” shaped 1,2,3-trisubstituted quinolizinone 34. Compound 34 (I)has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound 34 also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound 34 qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.

Journal of Medicinal Chemistry published new progress about Antitumor agents. 343338-28-3 belongs to class amides-buliding-blocks, name is (S)-2-Methylpropane-2-sulfinamide, and the molecular formula is C4H11NOS, Related Products of amides-buliding-blocks.

Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics

Heightman, Tom D. published the artcileDiscovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2, Product Details of C4H11NOS, the main research area is solid tumors ERK inhibitors ASTX029 clin metabolism physicochem pharmacokinetic.

Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clin. trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clin. candidate ASTX029 (15)(I) through structure-guided optimization of our previously published isoindolinone lead (7). The medicinal chem. campaign focused on addressing CYP3A4-mediated metabolism and maintaining favorable physicochem. properties. These efforts led to the identification of ASTX029, which showed the desired pharmacol. profile combining ERK1/2 inhibition with suppression of phospho-ERK1/2 (pERK) levels, and in addition, it possesses suitable preclin. pharmacokinetic properties predictive of once daily dosing in humans. ASTX029 is currently in a phase I-II clin. trial in patients with advanced solid tumors.

Journal of Medicinal Chemistry published new progress about Antitumor agents. 343338-28-3 belongs to class amides-buliding-blocks, name is (S)-2-Methylpropane-2-sulfinamide, and the molecular formula is C4H11NOS, Product Details of C4H11NOS.

Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics

Yan, Luping published the artcileStructure-Activity Relationships for the Marine Natural Product Sintokamides: Androgen Receptor N-Terminus Antagonists of Interest for Treatment of Metastatic Castration-Resistant Prostate Cancer, Quality Control of 343338-28-3, the main research area is marine sintokamide androgen receptor antagonist prostate cancer antitumor preparation.

Synthetic analogs of the marine natural product sintokamides have been prepared in order to investigate the structure-activity relationships for the androgen receptor N-terminal domain (AR NTD) antagonist activity of the sintokamide scaffold. An in vitro LNCaP cell-based transcriptional activity assay with an androgen-driven luciferase (Luc) reporter was used to monitor the potency of analogs. The data have shown that the chlorine atoms on the leucine side chains are essential for potent activity. Analogs missing the nonchlorinated Me groups of the leucine side chains (C-1 and C-17) are just as active and in some cases more active than the natural products. Analogs with the natural R configuration at C-10 and the unnatural R configuration at C-4 are most potent. Replacing the natural propionamide N-terminus cap with the more sterically hindered pivaloylamide N-terminus cap leads to enhanced potency. The tetramic acid fragment and the Me ether on the tetramic acid fragment are essential for activity. The SAR optimized analog 76 is more selective, easier to synthesize, more potent, and presumed to be more resistant to proteolysis than the natural sintokamides.

Journal of Natural Products published new progress about Antitumor agents. 343338-28-3 belongs to class amides-buliding-blocks, name is (S)-2-Methylpropane-2-sulfinamide, and the molecular formula is C4H11NOS, Quality Control of 343338-28-3.

Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics

Link, John O. published the artcileClinical targeting of HIV capsid protein with a long-acting small molecule, COA of Formula: C4H11NOS, the main research area is HIV infection capsid protein antiviral GS6207 viral replication cycle.

Abstract: Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis1-5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance6. In addition, suboptimal adherence to oral daily regimens can neg. affect the outcome of treatment-which contributes to virol. failure, resistance generation and viral transmission-as well as of pre-exposure prophylaxis, leading to new infections1,2,4,7-9. Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and addnl. can improve adherence10. Here we describe GS-6207, a small mol. that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the s.c. injection site. Drawing on X-ray crystallog. information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clin. studies, monotherapy with a single s.c. dose of GS-6207 (450 mg) resulted in a mean log10-transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 mo. These results provide clin. validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV.

Nature (London, United Kingdom) published new progress about Antiviral agents. 343338-28-3 belongs to class amides-buliding-blocks, name is (S)-2-Methylpropane-2-sulfinamide, and the molecular formula is C4H11NOS, COA of Formula: C4H11NOS.

Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics

Turdi, Huji published the artcileScreening Hit to Clinical Candidate: Discovery of BMS-963272, a Potent, Selective MGAT2 Inhibitor for the Treatment of Metabolic Disorders, SDS of cas: 343338-28-3, the main research area is MGAT2 inhibitor metabolic disorder aryl dihydropyridinone.

MGAT2 inhibition is a potential therapeutic approach for the treatment of metabolic disorders. High-throughput screening of the BMS internal compound collection identified the aryl dihydropyridinone compound 1 (hMGAT2 IC50 = 175 nM) as a hit. Compound 1 had moderate potency against human MGAT2, was inactive vs mouse MGAT2 and had poor microsomal metabolic stability. A novel chem. route was developed to synthesize aryl dihydropyridinone analogs to explore structure-activity relationship around this hit, leading to the discovery of potent and selective MGAT2 inhibitors 21f, 21s, and 28e that are stable to liver microsomal metabolism After triaging out 21f due to its inferior in vivo potency, pharmacokinetics, and structure-based liabilities and tetrazole 28e due to its inferior channel liability profile, 21s (BMS-963272) was selected as the clin. candidate following demonstration of on-target weight loss efficacy in the diet-induced obese mouse model and an acceptable safety and tolerability profile in multiple preclin. species.

Journal of Medicinal Chemistry published new progress about Body weight loss. 343338-28-3 belongs to class amides-buliding-blocks, name is (S)-2-Methylpropane-2-sulfinamide, and the molecular formula is C4H11NOS, SDS of cas: 343338-28-3.

Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics

Lundrigan, Travis published the artcileEnantioselective Imine Reduction Catalyzed by Phosphenium Ions, Recommanded Product: (S)-2-Methylpropane-2-sulfinamide, the main research area is diazophosphenium triflate cation preparation reduction catalyst; enantioselective imine reduction aryl heteroaryl pyrrolidine piperidine.

The first use of phosphenium cations in asym. catalysis is reported. A diazaphosphenium triflate, prepared in two or three steps on a multigram scale from com. available materials, catalyzes the hydroboration or hydrosilylation of cyclic imines with enantiomeric ratios of up to 97:3. Catalyst loadings are as low as 0.2 mol %. Twenty-two aryl/heteroaryl pyrrolidines and piperidines were prepared using this method. Imines containing functional groups such as thiophenes or pyridyl rings that can challenge transition-metal catalysts were reduced employing these systems.

Journal of the American Chemical Society published new progress about Crystal structure. 343338-28-3 belongs to class amides-buliding-blocks, name is (S)-2-Methylpropane-2-sulfinamide, and the molecular formula is C4H11NOS, Recommanded Product: (S)-2-Methylpropane-2-sulfinamide.

Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics

Xin, Bo-Tao published the artcileStructure-based design of inhibitors selective for human proteasome β2c or β2i subunits, Safety of (S)-2-Methylpropane-2-sulfinamide, the main research area is proteasome beta 2c 2i subunit inhibitor crystal structure.

Subunit-selective proteasome inhibitors are valuable tools to assess the biol. and medicinal relevance of individual proteasome active sites. Whereas the inhibitors for the β1c, β1i, β5c, and β5i subunits exploit the differences in the substrate-binding channels identified by X-ray crystallog., compounds selectively targeting β2c or β2i could not yet be rationally designed because of the high structural similarity of these two subunits. Here, we report the development, chem. synthesis, and biol. screening of a compound library that led to the identification of the β2c- and β2i-selective compounds LU-002c (4 (I); IC50 β2c: 8 nM, IC50 β2i/β2c: 40-fold) and LU-002i (5 (II); IC50 β2i: 220 nM, IC50 β2c/β2i: 45-fold), resp. Co-crystal structures with β2 humanized yeast proteasomes visualize protein-ligand interactions crucial for subunit specificity. Altogether, organic syntheses, activity-based protein profiling, yeast mutagenesis, and structural biol. allowed us to decipher significant differences of β2 substrate-binding channels and to complete the set of subunit-selective proteasome inhibitors.

Journal of Medicinal Chemistry published new progress about Crystal structure. 343338-28-3 belongs to class amides-buliding-blocks, name is (S)-2-Methylpropane-2-sulfinamide, and the molecular formula is C4H11NOS, Safety of (S)-2-Methylpropane-2-sulfinamide.

Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics

Ladduwahetty, Tammy published the artcileIdentification of a Potent, Selective, and Brain-Penetrant Rho Kinase Inhibitor and its Activity in a Mouse Model of Huntington’s Disease, Application of (S)-2-Methylpropane-2-sulfinamide, the main research area is piperazine analog preparation Rho kinase inhibitor SAR docking pharmacokinetics.

The Rho kinase (ROCK) pathway is implicated in the pathogenesis of several conditions, including neurol. diseases. In Huntington’s disease (HD), ROCK is implicated in mutant huntingtin (HTT) aggregation and neurotoxicity, and members of the ROCK pathway are increased in HD mouse models and patients. To validate this mode of action as a potential treatment for HD, a potent, selective, central nervous system (CNS)-penetrant ROCK inhibitor was sought. Identifying a compound that could be dosed orally in mice with selectivity against other AGC kinases, including protein kinase G (PKG), whose inhibition could potentially activate the ROCK pathway, was paramount for the program. The optimization of published ligands to identify a novel series of ROCK inhibitors based on a piperazine core was demonstrated. Morphing of the early series developed inhouse by scaffold hopping enabled the identification of a compound exhibiting high potency and desired selectivity and demonstrating a robust pharmacodynamic (PD) effect by the inhibition of ROCK-mediated substrate (MYPT1) phosphorylation after oral dosing.

Journal of Medicinal Chemistry published new progress about Molecular docking. 343338-28-3 belongs to class amides-buliding-blocks, name is (S)-2-Methylpropane-2-sulfinamide, and the molecular formula is C4H11NOS, Application of (S)-2-Methylpropane-2-sulfinamide.

Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics

Cao, Hengyi published the artcileDiscovery of new small molecule inhibitors targeting isocitrate dehydrogenase 1 (IDH1) with blood-brain barrier penetration, Formula: C4H11NOS, the main research area is glioblastoma antitumor pharmacokinetics isocitrate dehydrogenase 1 blood brain barrier; Acute myeloid leukemia; Blood-brain barrier; Cancer therapy; Glioblastoma; Isocitrate dehydrogenase 1; Small molecule inhibitors.

Isocitrate dehydrogenase 1 (IDH1), which catalyzes the conversion of isocitrate to α-ketoglutarate, is one of key enzymes in the tricarboxylic acid cycle (TCA). Hotspot mutation at Arg132 in IDH1 that alters the function of IDH1 by further converting the α-ketoglutarate(α-KG) to 2-hydroxyglutarate (2-HG) have been identified in a variety of cancers. Because the IDH1 mutations occur in a significant portion of gliomas and glioblastomas, it is important that IDH1 inhibitors have to be brain penetrant to treat IDH1-mutant brain tumors. Here we report the efforts to design and synthesize a novel serial of mutant IDH1 inhibitors with improved activity and the blood-brain barrier (BBB) penetration. We show that compound 5, (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(7-(trifluoromethyl)4,5-dihydroimidazo[1,5-a]quinolin-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one [2379528-08-0], exhibits good brain exposure and potent 2-HG inhibition in a HT1080-derived mouse xenograft model, which makes it a potential preclin. candidate to treat IDH1-mutant brain tumors.

European Journal of Medicinal Chemistry published new progress about Antitumor agents. 343338-28-3 belongs to class amides-buliding-blocks, name is (S)-2-Methylpropane-2-sulfinamide, and the molecular formula is C4H11NOS, Formula: C4H11NOS.

Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics

Li, Sizhe published the artcileStereospecific Synthesis of Glycoside Mimics Through Migita-Kosugi-Stille Cross-Coupling Reactions of Chemically and Configurationally Stable 1-C-Tributylstannyl Iminosugars, Name: (S)-2-Methylpropane-2-sulfinamide, the main research area is iminosugar glycoside mimic stereospecific synthesis; Migita Kosugi Stille coupling configurational stable tributylstannyl iminosugar.

A process for the de novo synthesis of imino-C-glycosides is described. The methodol. is based on the reaction of 1-C-stannylated iminosugars with various electrophiles under the conditions of Migita-Kosugi-Stille cross-couplings, which gives 1-C-substituted iminosugar derivatives in a stereoretentive process. The required iminoglycosyl stannanes are obtained by way of the highly stereoselective addition of tributylstannyllithium to (SR)- or (SS)-N-tert-butanesulfinyl glycosylamines, followed by an activation cyclization sequence. Most interestingly, the methodol. is tunable: the configuration of the tin adduct is controlled exclusively by the tert-butanesulfinyl auxiliary, thus giving access after ring formation to ‘α’-configured or ‘β’-configured iminoglycosyl stannanes. With the subsequent stereoretentive C-C bond-forming process, the methodol. allows the synthesis of pseudo anomers of imino-C-glycosyl compounds in a controlled fashion.

Advanced Synthesis & Catalysis published new progress about Addition reaction. 343338-28-3 belongs to class amides-buliding-blocks, name is (S)-2-Methylpropane-2-sulfinamide, and the molecular formula is C4H11NOS, Name: (S)-2-Methylpropane-2-sulfinamide.

Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics