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We are please to inform our readers that Chemistry Information site would be adding the Letters in Medicinal Chemistry articles soon. This newly launched journal is published by American Chemical Society.
Publication year: 2009
Source: Bioorganic & Medicinal Chemistry, In Press, Accepted Manuscript, Available online 17 October 2009
Kenji, Yoshikawa , Shozo, Kobayashi , Yumi, Nakamoto , Noriyasu, Haginoya , Satoshi, Komoriya , …
A series of cis-1,2-diaminocyclohexane derivatives possessing a 6-6 fused ring for the S1 moiety were synthesized as novel factor Xa (fXa) inhibitors. The synthesis, structure activity relationship (SAR), and physicochemical properties are reported herein, together with the discovery of compound 45c, which has potent anti-fXa activity, good physicochemical properties and pharmacokinetic (PK) profiles, including a reduced negative food effect.
Publication year: 2009
Source: Bioorganic & Medicinal Chemistry, In Press, Accepted Manuscript, Available online 16 October 2009
Mads Corvinius, Nielsen , Jonas, Borch , Trond, Ulven
A series of 4,7-diamino-1,10-phenanthroline derivatives carrying positively charged side chains has been synthesized, and their G-quadruplex interaction evaluated by circular dichroism (CD) and surface plasmon resonance (SPR). In absence of side chains, 4,7-diamino-1,10-phenanthroline exhibits a weak but significant G-quadruplex stabilizing effect, compared to no stabilization by 1,10-phenanthroline. We hypothesize that this effect is due to increased basicity of the phenanthroline nitrogens and protonation or ion chelation to form a central positive charge which stack on the G-tetrad above the central ionic column. Introduction of positively charged side chains results in compounds with appreciable G-quadruplex stabilizing properties and high aqueous solubility,…
Publication year: 2009
Source: Bioorganic & Medicinal Chemistry, In Press, Accepted Manuscript, Available online 16 October 2009
Andreas, Koeberle , Eva-Maria, Haberl , Antonietta, Rossi , Carlo, Pergola , Friederike, Dehm , …
Selective inhibition of pro-inflammatory prostaglandin (PG)E2 formation via microsomal PGE2 synthase-1 (mPGES-1) might be superior over inhibition of all cyclooxygenase (COX)-derived products by non-steroidal anti-inflammatory drugs (NSAIDs) and coxibs. We recently showed that benzo[g]indol-3-carboxylates potently suppress leukotriene biosynthesis by inhibiting 5-lipoxygenase. Here, we describe the discovery of benzo[g]indol-3-carboxylates as a novel class of potent mPGES-1 inhibitors (IC50 ⩾ 0.1 μM). Ethyl 2-(3-chlorobenzyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (compound 7a) inhibits human mPGES-1 in a cell-free assay (IC50 = 0.6 μM) as well as in intact A549 cells (IC50 = 2 μM), and suppressed PGE2 pleural levels in rat carrageenan-induced pleurisy. Inhibition of cellular COX-1/2 activity…
Publication year: 2009
Source: Bioorganic & Medicinal Chemistry, In Press, Accepted Manuscript, Available online 16 October 2009
Shikui, Zhao , Weicheng, Zhou , Jun, liu
A novel series of 2-cyclopropyl-4-thiophenyl quinoline-based mevalonolactones were synthesized from the substituted anilines by several reactions. Among them, (4R,6S)-6-[(E)-2-(2-cyclopropyl-6-fluoro-4-(4-fluoro-thiophenyl)-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (1d), (4R,6S)-6-[(E)-2-(2-cyclopropyl-6-fluoro-4-(3-methoxy-thiophenyl)-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (1f) and (4R,6S)-6-[(E)-2-(2-cyclopropyl-6-fluoro-4,7-di(3-methoxy-thiophenyl)-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (1q) showed potent HMG-CoA reductase inhibitory activity comparable with pitavastatin.
Publication year: 2009
Source: Bioorganic & Medicinal Chemistry, In Press, Accepted Manuscript, Available online 16 October 2009
Yerra Koteswara, Rao , Shih-Hua, Fang , Yew-Min, Tzeng
A series of twenty three 3′,4′,5′-trimethoxychalcone analogues was synthesized and their inhibitory effects on nitric oxide (NO) production in LPS/IFN-γ-treated macrophages, and tumor cell proliferation has been investigated. 4-hydroxy-3,3′,4′,5′-tetramethoxychalcone (7), 3,4-dihydroxy-3′,4′,5′-trimethoxychalcone (11), 3-hydroxy-3′,4,4′,5′-tetramethoxychalcone (14), and 3,3′,4′,5′-tetramethoxychalcone (15) were the most potent growth inhibitory agents on NO production, with an IC50 value of 0.3, 1.5, 1.3 and 0.3 μM, respectively. The tumor cells proliferation assay results revealed that several compounds exhibited potent inhibition activity against different cancer cell lines. The chalcone 15 was the most potent anti-proliferative compound in the series with IC50 values of 1.8 and 2.2 μM toward liver…
Publication year: 2009
Source: Bioorganic & Medicinal Chemistry, In Press, Accepted Manuscript, Available online 16 October 2009
Kenji, Yoshikawa , Aki, Yokomizo , Hiroyuki, Naito , Noriyasu, Haginoya , Shozo, Kobayashi , …
A series of cis-1,2-diaminocyclohexane derivatives were synthesized with the aim of optimizing previously disclosed factor Xa (fXa) inhibitors. The exploration of 5-6 fused rings as alternative S1 moieties resulted in two compounds which demonstrated improved solubility and reduced food effect compared to the clinical candidate, compound A. Herein, we describe the synthesis and structure activity relationship (SAR), together with the physicochemical properties and pharmacokinetic (PK) profiles of some prospective compounds.
Publication year: 2009
Source: Bioorganic & Medicinal Chemistry, In Press, Accepted Manuscript, Available online 16 October 2009
Kaname, Isozaki , Jinglan, Li , Kazushi, Okada , Hirokazu, Nishimura , Ayami, Matsushima , …
[Arg14,Lys15]Nociceptin is a very potent for ORL1 receptor, showing a few times stronger binding activity and much more enhanced biological activity than endogenous nociceptin. This synergistic outcome has been suggested to be due to the interaction with the receptor aromatic and/or acidic amino acid residues crucial to receptor activation. In order to identify such receptor residues in the second ORL1 extracellular loop, we prepared a series of recombinant mutant receptors. The mutant receptor Gln205Ala was found to be as active as wild-type ORL1 for both nociceptin and [Arg14,Lys15]nociceptin. In contrast, Asp206Ala and Tyr207Ala exhibited considerably reduced activity for [Arg14,Lys15]nociceptin, exhibiting…
Publication year: 2009
Source: Bioorganic & Medicinal Chemistry, In Press, Accepted Manuscript, Available online 15 October 2009
Atsushi, Miyazaki , Magne O., Sydnes , Minoru, Isobe , Hiroshi, Ohinata , Motoi, Miyazu , …
Protein phosphatase 1g, a serine/threonine phosphatase, is a metalloprotein that coordinates two Mn2+ in the active site when expressed in E. coli in a buffer containing MnCl2. Herein, we report on the oxidatively induced copper for manganese exchange in protein phosphatase 1g, thus enabling firm confirmation of the four histidine (His) amino acid residues (His66, His125, His173, and His248) involved in metal coordination. By exchanging manganese with copper the oxidation yields for the peptides increased dramatically, thus simplifying detection of the oxidized peptides and analysis of the oxidation sites within the oxidized peptides. We also found that when copper was…
Publication year: 2009
Source: Bioorganic & Medicinal Chemistry, In Press, Accepted Manuscript, Available online 15 October 2009
L. Nathan, Tumey , Niala, Bhagirath , Agnes, Brennan , Natasja, Brooijmans , Julie, Lee , …
PKCθ is a serine/threonine kinase involved in the regulation of IL2 production in T cells. It has recently become an attractive therapeutic target for a variety of immunological disorders. We describe the optimization of the enzymatic and cellular potency of a series of 5-vinyl-3-pyridinecarbonitrile inhibitors of PKCθ. A binding model was developed that explains much of the SAR observed for this series, including the enzymatic potency observed for 19. An analysis of functional potency against various physiochemical parameters suggests that cellular potency is correlated with LogD7.4, but not with cLogP, PAMPA permeability, or TPSA.
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