Publications by authors named "Kumaravel Selvakumar"

BMS-813160 (compound ) was identified as a potent and selective CCR2/5 dual antagonist. Compound displayed good permeability at pH = 7.4 in PAMPA experiments and demonstrated excellent human liver microsome stability.

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The oxycyclohexyl acid BMS-986278 () is a potent lysophosphatidic acid receptor 1 (LPA) antagonist, with a human LPA of 6.9 nM. The structure-activity relationship (SAR) studies starting from the LPA antagonist clinical compound BMS-986020 (), which culminated in the discovery of , are discussed.

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Article Synopsis
  • - RORγt is a key nuclear receptor that influences the production of pro-inflammatory cytokines like IL-17 and IL-22, making it a target for treating immunological conditions such as psoriasis and inflammatory bowel diseases.
  • - Researchers developed a new series of tricyclic RORγt inverse agonists that exhibited better in vitro activity in various assays compared to earlier compounds.
  • - The most promising molecule from pharmacokinetic studies showed strong effects in mouse models of psoriasis, proving its potential as a biological treatment option.
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An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2.

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In solving the P-gp and BCRP transporter-mediated efflux issue in a series of benzofuran-derived pan-genotypic palm site inhibitors of the hepatitis C virus NS5B replicase, it was found that close attention to physicochemical properties was essential. In these compounds, where both molecular weight (MW >579) and TPSA (>110 Å) were high, attenuation of polar surface area together with weakening of hydrogen bond acceptor strength of the molecule provided a higher intrinsic membrane permeability and more desirable Caco-2 parameters, as demonstrated by trifluoroacetamide and the benchmark -ethylamino analog . In addition, the tendency of these inhibitors to form intramolecular hydrogen bonds potentially contributes favorably to the improved membrane permeability and absorption.

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The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile.

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Certain aromatic nitriles are well-known inhibitors of cysteine proteases. The mode of action of these compounds involves the formation of a reversible or irreversible covalent bond between the nitrile and a thiol group in the active site of the enzyme. However, the reactivity of these aromatic nitrile-substituted heterocycles may lead inadvertently to nonspecific interactions with DNA, protein, glutathione, and other endogenous components, resulting in toxicity and complicating the use of these compounds as therapeutic agents.

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The title reaction has been surveyed for a number of substrates with differing substitution patterns. With a few exceptions, the methodology provides a one-pot synthesis of the 1,2-diamines from widely available and inexpensive starting materials, and in high yields. In addition, the coupling of 1,4- and 1,3-bis-(N,N,N',N'-tetraalkyl)arylenediamides is shown, under the same experimental conditions, to yield oligomers: R2NC(O)C6H4CH(NR2)-[CH(NR2)C6H4CH(NR2)]n-CH(NR2)C6H4C(O)-NR2 (R = methyl and ethyl; n = 0 to ca.

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The first monocarbenepalladium(0) complexes with benzoquinone and naphthoquinone as additional ligands have been prepared. As demonstrated by NMR spectroscopy and X-ray analysis, the complexes show a unique coordination mode giving quinone-bridged dimers. The monocarbenepalladium(0) complexes allow efficient cross-coupling reactions of aryldiazonium salts with olefins (Heck reaction) and arylboronic acids (Suzuki reaction).

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[reaction: see text] The Heck reaction of aryl chlorides was investigated in the presence of defined monocarbenepalladium(0) complexes. Activated and nonactivated aryl chlorides provide the corresponding cinnamic esters and stilbenes in (n)Bu(4)NBr as a ionic liquid in good to excellent yields.

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A sequence of reduction, deoxygenation, and coupling steps results in a remarkable reaction, which represents an important new method for the synthesis of 1,2-diamines. The vicinal diamines are formed by the facile coupling of aromatic amides in the presence of titanocene catalysts and PhMeSiH .

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