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Katherine L Lee,
Megan A Foley,
Lihren Chen,
Mark L Behnke, Frank E Lovering,
Steven J Kirincich,
Weiheng Wang,
Jaechul Shim,
Steve Tam,
Marina W H Shen,
Soopeang Khor,
Xin Xu,
Debra G Goodwin,
Manjunath K Ramarao,
Cheryl Nickerson-Nutter,
Frances Donahue,
M Sherry Ku,
James D Clark,
John C McKew
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ABSTRACT: The synthesis and structure-activity relationship of a series of indole inhibitors of cytosolic phospholipase A2alpha (cPLA2alpha, type IVA phospholipase) are described. Inhibitors of cPLA2alpha are predicted to be efficacious in treating asthma as well as the signs and symptoms of osteoarthritis, rheumatoid arthritis, and pain. The introduction of a benzyl sulfonamide substituent at C2 was found to impart improved potency of these inhibitors, and the SAR of these sulfonamide analogues is disclosed. Compound 123 (Ecopladib) is a sub-micromolar inhibitor of cPLA2alpha in the GLU micelle and rat whole blood assays. Compound 123 displayed oral efficacy in the rat carrageenan air pouch and rat carrageenan-induced paw edema models.
Journal of Medicinal Chemistry 04/2007; 50(6):1380-400. · 5.25 Impact Factor
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ABSTRACT: By focusing on the P1 portion of the piperidine beta-sulfone ligands we identified a motif that induces selectivity and resulted in a series of TACE inhibitors that demonstrated excellent in vitro potency against isolated TACE enzyme and excellent selectivity over MMPs 1, 2, 9, 13, and 14.
Bioorganic & Medicinal Chemistry Letters 02/2007; 17(1):34-9. · 2.55 Impact Factor
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Derek C Cole,
Eric S Manas,
Joseph R Stock,
Jeffrey S Condon,
Lee D Jennings,
Ann Aulabaugh,
Rajiv Chopra,
Rebecca Cowling,
John W Ellingboe,
Kristi Y Fan, [......],
Michael S Malamas,
Mark L Stahl,
James Strand,
Mohani N Sukhdeo,
Kristine Svenson,
M James Turner,
Erik Wagner,
Junjun Wu,
Ping Zhou,
Jonathan Bard
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ABSTRACT: BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Abeta, which aggregates leading to plaque deposits implicated in Alzheimer's disease. We have identified small-molecule acylguanidine inhibitors of BACE1. Crystallographic studies show that these compounds form unique hydrogen-bonding interactions with the catalytic site aspartic acids and stabilize the protein in a flap-open conformation. Structure-based optimization led to the identification of potent analogs, such as 10d (BACE1 IC(50) = 110 nM).
Journal of Medicinal Chemistry 11/2006; 49(21):6158-61. · 5.25 Impact Factor
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John C McKew,
Megan A Foley,
Paresh Thakker,
Mark L Behnke, Frank E Lovering,
Fuk-Wah Sum,
Steve Tam,
Kun Wu,
Marina W H Shen,
Wen Zhang,
Mario Gonzalez,
Shanghao Liu,
Anu Mahadevan,
Howard Sard,
Soo Peang Khor,
James D Clark
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ABSTRACT: Compound 1 was previously reported to be a potent inhibitor of cPLA(2)alpha in both artificial monomeric substrate and cell-based assays. However, 1 was inactive in whole blood assays previously used to characterize cyclooxygenase and lipoxygenase inhibitors. The IC(50) of 1 increased dramatically with cell number or lipid/detergent concentration. In an attempt to insert an electrophilic ketone between the indole and benzoic acid moieties, we discovered that increasing the distance between the two moieties gave a compound with activity in the GLU (7-hydroxycoumarinyl-gamma-linolenate) micelle assay, which contains lipid and detergent. Extensive structure-activity relationship work around this lead identified a potent pharmacophore for cPLA(2)alpha inhibition. The IC(50)s between the GLU micelle and rat whole blood assays correlated highly. No correlation was found for other parameters, including lipophilicity or acidity of the required acid functionality. Compounds 25, 39, and 94 emerged as potent, selective inhibitors of cPLA(2)alpha and represent well-validated starting points for further optimization.
Journal of Medicinal Chemistry 02/2006; 49(1):135-58. · 5.25 Impact Factor
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John C. McKew,
Megan A. Foley,
Paresh Thakker,
Mark L. Behnke, Frank E. Lovering,
Fuk-Wah Sum,
Steve Tam,
Kun Wu,
Marina W. H. Shen,
Wen Zhang,
Mario Gonzalez,
Shanghao Liu,
Anu Mahadevan,
Howard Sard,
Soo Peang Khor,
James D. Clark
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ABSTRACT: Compound 1 was previously reported to be a potent inhibitor of cPLA2α in both artificial monomeric substrate and cell-based assays. However, 1 was inactive in whole blood assays previously used to characterize cyclooxygenase and lipoxygenase inhibitors. The IC50 of 1 increased dramatically with cell number or lipid/detergent concentration. In an attempt to insert an electrophilic ketone between the indole and benzoic acid moieties, we discovered that increasing the distance between the two moieties gave a compound with activity in the GLU (7-hydroxycoumarinyl-γ-linolenate) micelle assay, which contains lipid and detergent. Extensive structure−activity relationship work around this lead identified a potent pharmacophore for cPLA2α inhibition. The IC50s between the GLU micelle and rat whole blood assays correlated highly. No correlation was found for other parameters, including lipophilicity or acidity of the required acid functionality. Compounds 25, 39, and 94 emerged as potent, selective inhibitors of cPLA2α and represent well-validated starting points for further optimization.
12/2005;
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ABSTRACT: A potent, selective series of MMP-13 inhibitors has been derived from a weak (3.2 microM) inhibitor that did not bear a zinc chelator. Structure-based drug design strategies were employed to append a Zn-chelating group to one end of the molecule and functionality to enhance selectivity to the other. A compound from this series demonstrated rat oral bioavailability and efficacy in a bovine articular cartilage explant model.
Bioorganic & Medicinal Chemistry Letters 10/2005; 15(18):4105-9. · 2.55 Impact Factor
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04/2002;
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ABSTRACT: The 2-azaallyl anion route to pyrrolidines was used for the concise synthesis of alkaloids featuring the 3a-arylperhydroindole nucleus. The brevity and efficiency of the syntheses described are particularly notable. The key transformations involved the tin−lithium exchange of (2-azaallyl)stannanes to 2-azaallyl anions, which participated in intramolecular [π4s + π2s] cycloadditions with styrenes to produce the requisite 3a-arylperhydroindoles. (±)-Crinine was synthesized in eight steps in 20% overall yield, with the key cycloaddition producing a single stereoisomer of the perhydroindole in 80% yield. (±)-6-Epicrinine was an intermediate in this synthesis. The key cycloaddition involved the use of a diene as the anionophile. The first asymmetric syntheses of (−)-amabiline and (−)-augustamine were accomplished in overall yields of 43% (in eight steps) and 42% (in nine steps), respectively, confirming or determining the absolute stereochemistry of the natural products. The key cycloadditions produced the perhydroindoles in 83% and 74% yields, respectively, with reasonable stereocontrol. The highly stereoselective cycloaddition leading to a trans-dialkoxyperhydroindole in 75% yield was consistent with stereochemical predictions. These studies contribute to a growing body of knowledge on the scope and stereochemistry of 2-azaallyl anion cycloadditions.
04/1998;
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ABSTRACT: Transmetalation of the (2-azaallyl)stannane 9 with n-BuLi produced the 2-azaallyl anion 12 which underwent an intramolecular cycloaddition with an alkene to give the perhydroindole 10 in 80% yield as a single stereoisomer. Transformation of 10 to 6-epicrinine 2 and crinine 1 was readily accomplished. Peer Reviewed http://deepblue.lib.umich.edu/bitstream/2027.42/31137/1/0000034.pdf
