- 2,3-substituted 2-azanorbornanes as polar β-turn mimetics
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The design and synthesis of N-(3-indolylmethyl)-3-benzyl-2-azabicyclo[2.2.1]heptane-2-carboxamide (3) as a conformationally constrained non-peptide β-turn mimetic is described. Compound 3 is shown to mimic the Trp and Phe side chain conformation and the overall dipole moment of MEN10627 (2), a cyclic hexapeptide with a high NK-2 affinity. The tachykinin receptor affinities of 3 are evaluated and compared to those of MEN10627 and previously reported Trp-Phe mimetic 1.
- Horwell, David C.,Naylor, Dorica,Willems, Henriette M. G.
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- Enantioselective Syntheses of Strychnos and Chelidonium Alkaloids through Regio- and Stereocontrolled Cooperative Catalysis
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We describe enantioselective syntheses of strychnos and chelidonium alkaloids. In the first case, indole acetic acid esters were established as excellent partner nucleophiles for enantioselective cooperative isothiourea/Pd catalyzed α-alkylation. This provides products containing indole-bearing stereocenters in high yield and with excellent levels of enantioinduction in a manner that is notably independent of the N-substituent. This led to concise syntheses of (?)-akuammicine and (?)-strychnine. In the second case, the poor performance of ortho-substituted cinnamyl electrophiles in the enantioselective cooperative isothiourea/Ir catalyzed α-alkylation was overcome by appropriate substituent choice, leading to enantioselective syntheses of (+)-chelidonine, (+)-norchelidonine, and (+)-chelamine.
- Fyfe, James W. B.,Hutchings-Goetz, Luke S.,Snaddon, Thomas N.,Yang, Chao
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supporting information
p. 17556 - 17564
(2020/08/14)
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- Methods and Compositions for Treatment of Scleritis and Related Disorders
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The present teachings relate to the field of anti-inflammatory substances and more particularly to compounds that are useful for the treatment of scleritis, a scleritis symptom, or a scleritis-related disorder. In one aspect, methods of treating scleritis, a scleritis symptom, or a scleritis-related disorder generally include administering to a subject a compound of Formula I: or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein W1, W2, R1, L, X, Y, Z, and n1 are defined as described herein.
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Page/Page column 25-26
(2008/12/05)
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- Discovery and refinement of a new structural class of potent peptide deformylase inhibitors
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New classes of antibiotics are urgently needed to counter increasing levels of pathogen resistance. Peptide deformylase (PDF) was originally selected as a specific bacterial target, but a human homologue, the inhibition of which causes cell death, was rec
- Boularot, Adrien,Giglione, Carmela,Petit, Sylvain,Duroc, Yann,De Sousa, Rodolphe Alves,Larue, Valéry,Cresteil, Thierry,Dardel, Frédéric,Artaud, Isabelle,Meinnel, Thierry
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- 2-(4-Chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[H] quinoline-4-carboxylic acid (PSI-697): Identification of a clinical candidate from the quinoline salicylic acid series of P-selectin antagonists
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P-selectin-PSGL-1 interaction causes rolling of leukocytes on the endothelial cell surface, which subsequently leads to firm adherence and leukocyte transmigration through the vessel wall into the surrounding tissues. P-selectin is upregulated on the surface of both platelets and endothelium in a variety of atherosclerosis-associated conditions. Consequently, inhibition of this interaction by means of a small molecule P-selectin antagonist is an attractive strategy for the treatment of atherosclerosis. High-throughput screening and subsequent analoging had led to the identification of compound 1 as the lead candidate. Herein, we report the continuation of this work and the discovery of a second-generation series, the tetrahydrobenzoquinoline salicylic acids. These compounds have improved pharmacokinetic properties, and a number of them have shown oral efficacy in mouse and rat models of atherogenesis and vascular injury. The lead 31 (PSI-697), is currently in clinical development for the treatment of atherothrombotic vascular events.
- Kaila, Neelu,Janz, Kristin,Huang, Adrian,Moretto, Alessandro,DeBernardo, Silvano,Bedard, Patricia W.,Tam, Steve,Clerin, Valerie,Keith Jr., James C.,Tsao, Desirée H.H.,Sushkova, Natalia,Shaw, Gray D.,Camphausen, Raymond T.,Schaub, Robert G.,Wang, Qin
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- Methods and compositions for selectin inhibition
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The present invention relates to the field of anti-inflammatory substances, and more particularly to novel compounds that act as antagonists of the mammalian adhesion proteins known as selectins. In some embodiments, methods for treating selectin mediated disorders are provided which include administration of compound of Formula I: wherein the constituent variables are defined herein.
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Page/Page column 26
(2008/06/13)
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- Enantioselective synthesis of 2-substituted 3-aminopropanoic acid (β-alanine) derivatives which are β-analogues of aromatic amino acids
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3-Aminopropanoic acid derivatives with a phenyl, 4-hydroxyphenyl, benzyl or indol-3-yl substituent at C-2 can be prepared enantioselectively by routes involving electrophilic attack of synthetic equivalents of [H2NCH2]+ upon enolates derived from chiral 3-acyl-1,3-oxazolidin-2-ones. tert-Butyl bromoacetate may be used as the electrophile, with subsequent introduction of nitrogen through the Curtius reaction, using the sequence of reagents (i) CF3CO2H; (ii) (PhO)2P(O)N3, Et3N, PhCH2OH; alternatively, direct electrophilic reaction with 1-[N-(benzyloxycarbonyl)aminomethyl]benzotriazole 4c or benzyl N-(acetoxymechyl)carbamate 2d introduces a protected aminomethyl group in a single step.
- Arvanitis, Elena,Ernst, Holger,Ludwig, Alice A.,Robinson, Andrew J.,Wyatt, Peter B.
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p. 521 - 528
(2007/10/03)
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