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Robert W Marquis,
Amparo M Lago,
James F Callahan,
Robert E Lee Trout,
Maxine Gowen,
Eric G DelMar,
Bradford C Van Wagenen,
Sarah Logan,
Scott Shimizu,
John Fox,
Edward F Nemeth,
Zheng Yang,
Theresa Roethke,
Brian R Smith,
Keith W Ward,
John Lee, Richard M Keenan,
Pradip Bhatnagar
[show abstract]
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ABSTRACT: Functional screening of the former SmithKline Beecham compound collection against the human calcium receptor (CaR) resulted in the identification of the amino alcohol-based hit 2 (IC(50) = 11 microM). Structure-activity studies of 2 focused on the optimization of the right- and left-hand side aromatic moieties as well as the amino alcohol linker region. Critical to the optimization of this antagonist template was the discovery that the chirality of the C-2 secondary alcohol played a key role in enhancing both CaR potency as well as selectivity over the beta-adrenergic receptor subtypes. These SAR studies ultimately led to the identification of 38 (NPS 2143; SB-262470A), a potent and orally active CaR antagonist. Pharmacokinetic characterization of 38 in the rat revealed that this molecule had a large volume of distribution (11 L/kg), which resulted in a prolonged systemic exposure, protracted increases in the plasma levels of PTH, and an overall lack of net bone formation effect in a rodent model of osteoporosis.
Journal of Medicinal Chemistry 07/2009; 52(13):3982-93. · 4.80 Impact Factor
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Antony N Shaw,
Rosanna Tedesco,
Ramesh Bambal,
Deping Chai,
Nestor O Concha,
Michael G Darcy,
Dashyant Dhanak,
Kevin J Duffy,
Duke M Fitch,
Adam Gates,
Victor K Johnston, Richard M Keenan,
Juili Lin-Goerke,
Nannan Liu,
Robert T Sarisky,
Kenneth J Wiggall,
Michael N Zimmerman
[show abstract]
[hide abstract]
ABSTRACT: The synthesis and optimisation of HCV NS5B polymerase inhibitors with improved potency versus the existing compound 1 is described. Substitution in the benzothiadiazine portion of the molecule, furnishing improvement in potency in the high protein Replicon assay, is highlighted, culminating in the discovery of 12h, a highly potent oxyacetamide derivative.
Bioorganic & medicinal chemistry letters 06/2009; 19(15):4350-3. · 2.65 Impact Factor
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Rosanna Tedesco,
Deping Chai,
Michael G Darcy,
Dashyant Dhanak,
Duke M Fitch,
Adam Gates,
Victor K Johnston, Richard M Keenan,
Juili Lin-Goerke,
Robert T Sarisky,
Antony N Shaw,
Klara L Valko,
Kenneth J Wiggall,
Michael N Zimmerman,
Kevin J Duffy
[show abstract]
[hide abstract]
ABSTRACT: Modification of the benzo rings of 3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones into heteroaromatic systems was investigated to enhance physicochemical properties and potency profile of this class of inhibitors. The synthesis and biological activity of the derived compounds is discussed.
Bioorganic & medicinal chemistry letters 06/2009; 19(15):4354-8. · 2.65 Impact Factor
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Dirk A Heerding,
Nelson Rhodes,
Jack D Leber,
Tammy J Clark, Richard M Keenan,
Louis V Lafrance,
Mei Li,
Igor G Safonov,
Dennis T Takata,
Joseph W Venslavsky, [......],
Derek R Duckett,
Derek Eberwein,
Victoria B Knick,
Timothy J Lansing,
Randy T McConnell,
Shuyun Zhang,
Elisabeth A Minthorn,
Nestor O Concha,
Gregory L Warren,
Rakesh Kumar
[show abstract]
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ABSTRACT: Overexpression of AKT has an antiapoptotic effect in many cell types, and expression of dominant negative AKT blocks the ability of a variety of growth factors to promote survival. Therefore, inhibitors of AKT kinase activity might be useful as monotherapy for the treatment of tumors with activated AKT. Herein, we describe our lead optimization studies culminating in the discovery of compound 3g (GSK690693). Compound 3g is a novel ATP competitive, pan-AKT kinase inhibitor with IC 50 values of 2, 13, and 9 nM against AKT1, 2, and 3, respectively. An X-ray cocrystal structure was solved with 3g and the kinase domain of AKT2, confirming that 3g bound in the ATP binding pocket. Compound 3g potently inhibits intracellular AKT activity as measured by the inhibition of the phosphorylation levels of GSK3beta. Intraperitoneal administration of 3g in immunocompromised mice results in the inhibition of GSK3beta phosphorylation and tumor growth in human breast carcinoma (BT474) xenografts.
Journal of Medicinal Chemistry 10/2008; 51(18):5663-79. · 4.80 Impact Factor
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Jian Jin,
Ming An,
Anthony Sapienza,
Nambi Aiyar,
Diane Naselsky,
Henry M Sarau,
James J Foley,
Kevin L Salyers,
Steven D Knight, Richard M Keenan,
Ralph A Rivero,
Dashyant Dhanak,
Stephen A Douglas
[show abstract]
[hide abstract]
ABSTRACT: SAR exploration of the central diamine, benzyl, and terminal aminoalkoxy regions of the N-cyclic azaalkyl benzamide series led to the identification of very potent human urotensin-II receptor antagonists such as 1a with a K(i) of 4 nM. The synthesis and structure-activity relationships (SAR) of N-cyclic azaalkyl benzamides are described.
Bioorganic & medicinal chemistry letters 08/2008; 18(14):3950-4. · 2.65 Impact Factor
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[show abstract]
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ABSTRACT: A novel benzimidazole series of small-molecule thrombopoietin receptor agonists has been discovered. Herein, we discuss the preliminary exploration of structure-activity relationships within this chemotype.
Bioorganic & Medicinal Chemistry Letters 04/2006; 16(5):1212-6. · 2.55 Impact Factor
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Rosanna Tedesco,
Antony N Shaw,
Ramesh Bambal,
Deping Chai,
Nestor O Concha,
Michael G Darcy,
Dashyant Dhanak,
Duke M Fitch,
Adam Gates,
Warren G Gerhardt, [......],
Glenn A Hofmann,
Victor K Johnston,
Arun C Kaura,
Nannan Liu, Richard M Keenan,
Juili Lin-Goerke,
Robert T Sarisky,
Kenneth J Wiggall,
Michael N Zimmerman,
Kevin J Duffy
[show abstract]
[hide abstract]
ABSTRACT: Recently, we disclosed a new class of HCV polymerase inhibitors discovered through high-throughput screening (HTS) of the GlaxoSmithKline proprietary compound collection. This interesting class of 3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones potently inhibits HCV polymerase enzymatic activity and inhibits the ability of the subgenomic HCV replicon to replicate in Huh-7 cells. This report will focus on the structure-activity relationships (SAR) of substituents on the quinolinone ring, culminating in the discovery of 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone (130), an inhibitor with excellent potency in biochemical and cellular assays possessing attractive molecular properties for advancement as a clinical candidate. The potential for development and safety assessment profile of compound 130 will also be discussed.
Journal of Medicinal Chemistry 03/2006; 49(3):971-83. · 5.25 Impact Factor
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Stephen A Douglas,
David J Behm,
Nambi V Aiyar,
Diane Naselsky,
Jyoti Disa,
David P Brooks,
Eliot H Ohlstein,
John G Gleason,
Henry M Sarau,
James J Foley, [......],
Katherine Widdowson,
Graham Riley,
Jian Jin,
Timothy F Gallagher,
Stanley J Schmidt,
Lance Ridgers,
Lisa T Christmann, Richard M Keenan,
Steven D Knight,
Dashyant Dhanak
[show abstract]
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ABSTRACT: 1. SB-706375 potently inhibited [(125)I]hU-II binding to both mammalian recombinant and 'native' UT receptors (K(i) 4.7+/-1.5 to 20.7+/-3.6 nM at rodent, feline and primate recombinant UT receptors and K(i) 5.4+/-0.4 nM at the endogenous UT receptor in SJRH30 cells). 2. Prior exposure to SB-706375 (1 microM, 30 min) did not alter [(125)I]hU-II binding affinity or density in recombinant cells (K(D) 3.1+/-0.4 vs 5.8+/-0.9 nM and B(max) 3.1+/-1.0 vs 2.8+/-0.8 pmol mg(-1)) consistent with a reversible mode of action. 3. The novel, nonpeptidic radioligand [(3)H]SB-657510, a close analogue of SB-706375, bound to the monkey UT receptor (K(D) 2.6+/-0.4 nM, B(max) 0.86+/-0.12 pmol mg(-1)) in a manner that was inhibited by both U-II isopeptides and SB-706375 (K(i) 4.6+/-1.4 to 17.6+/-5.4 nM) consistent with the sulphonamides and native U-II ligands sharing a common UT receptor binding domain. 4. SB-706375 was a potent, competitive hU-II antagonist across species with pK(b) 7.29-8.00 in HEK293-UT receptor cells (inhibition of [Ca(2+)](i)-mobilization) and pK(b) 7.47 in rat isolated aorta (inhibition of contraction). SB-706375 also reversed tone established in the rat aorta by prior exposure to hU-II (K(app) approximately 20 nM). 5. SB-706375 was a selective U-II antagonist with >/=100-fold selectivity for the human UT receptor compared to 86 distinct receptors, ion channels, enzymes, transporters and nuclear hormones (K(i)/IC(50)>1 microM). Accordingly, the contractile responses induced in isolated aortae by KCl, phenylephrine, angiotensin II and endothelin-1 were unaltered by SB-706375 (1 microM). 6. In summary, SB-706375 is a high-affinity, surmountable, reversible and selective nonpeptide UT receptor antagonist with cross-species activity that will assist in delineating the pathophysiological actions of U-II in mammals.
British Journal of Pharmacology 08/2005; 145(5):620-35. · 4.41 Impact Factor
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Jian Jin,
Dashyant Dhanak,
Steven D Knight,
Katherine Widdowson,
Nambi Aiyar,
Diane Naselsky,
Henry M Sarau,
James J Foley,
Dulcie B Schmidt,
Carl D Bennett,
Bing Wang,
Gregory L Warren,
Michael L Moore, Richard M Keenan,
Ralph A Rivero,
Stephen A Douglas
[show abstract]
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ABSTRACT: High throughput screening of the corporate compound collection led to the discovery of a novel series of substituted aminoalkoxybenzyl pyrrolidines as human urotensin-II receptor antagonists. The synthesis, initial structure-activity relationships, and optimization of the initial hit that led to the identification of a truncated sub-series, represented by SB-436811 (1a), are described.
Bioorganic & Medicinal Chemistry Letters 08/2005; 15(13):3229-32. · 2.55 Impact Factor
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George Burton,
Thomas W Ku,
Thomas J Carr,
Terry Kiesow,
Robert T Sarisky,
Juili Lin-Goerke,
Audrey Baker,
David L Earnshaw,
Glenn A Hofmann, Richard M Keenan,
Dashyant Dhanak
[show abstract]
[hide abstract]
ABSTRACT: HTS of the compound collection for inhibition of the HCV RNA dependent RNA polymerase identified two 168 member N-acyl pyrrolidine combinatorial mixture hits. Deconvolution and expansion of these mixtures by solid phase synthesis to establish initial SAR and identify a potent inhibitor is reported.
Bioorganic & Medicinal Chemistry Letters 04/2005; 15(6):1553-6. · 2.55 Impact Factor
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Michael L Doyle,
Shin-Shay Tian,
Stephen G Miller,
Linda Kessler,
Audrey E Baker,
Michael R Brigham-Burke,
Susan B Dillon,
Kevin J Duffy, Richard M Keenan,
Ruth Lehr,
Jon Rosen,
Lumelle A Schneeweis,
John Trill,
Peter R Young,
Juan I Luengo,
Peter Lamb
[show abstract]
[hide abstract]
ABSTRACT: Granulocyte colony-stimulating factor regulates neutrophil production by binding to a specific receptor, the granulocyte colony-stimulating factor receptor, expressed on cells of the granulocytic lineage. Recombinant forms of granulocyte colony-stimulating factor are used clinically to treat neutropenias. As part of an effort to develop granulocyte colony-stimulating factor mimics with the potential for oral bioavailability, we previously identified a nonpeptidyl small molecule (SB-247464) that selectively activates murine granulocyte colony-stimulating factor signal transduction pathways and promotes neutrophil formation in vivo. To elucidate the mechanism of action of SB-247464, a series of cell-based and biochemical assays were performed. The activity of SB-247464 is strictly dependent on the presence of zinc ions. Titration microcalorimetry experiments using a soluble murine granulocyte colony-stimulating factor receptor construct show that SB-247464 binds to the extracellular domain of the receptor in a zinc ion-dependent manner. Analytical ultracentrifugation studies demonstrate that SB-247464 induces self-association of the N-terminal three-domain fragment in a manner that is consistent with dimerization. SB-247464 induces internalization of granulocyte colony-stimulating factor receptor on intact cells, consistent with a mechanism involving receptor oligomerization. These data show that small nonpeptidyl compounds are capable of selectively binding and inducing productive oligomerization of cytokine receptors.
Journal of Biological Chemistry 04/2003; 278(11):9426-34. · 4.77 Impact Factor
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Dashyant Dhanak,
Kevin J Duffy,
Victor K Johnston,
Juili Lin-Goerke,
Michael Darcy,
Antony N Shaw,
Baohua Gu,
Carol Silverman,
Adam T Gates,
Michael R Nonnemacher, [......],
Derrick Maley,
Alfred DelVecchio,
Ricardo Macarron,
Glenn A Hofmann,
Zaid Alnoah,
Hung-Yuan Cheng,
George Chan,
Sanjay Khandekar, Richard M Keenan,
Robert T Sarisky
[show abstract]
[hide abstract]
ABSTRACT: The hepatitis C virus (HCV) NS5B protein encodes an RNA-dependent RNA polymerase (RdRp), the primary catalytic enzyme of the HCV replicase complex. We established a biochemical RNA synthesis assay, using purified recombinant NS5B lacking the C-terminal 21 amino acid residues, to identify potential polymerase inhibitors from a high throughput screen of the GlaxoSmithKline proprietary compound collection. The benzo-1,2,4-thiadiazine compound 1 was found to be a potent, highly specific inhibitor of NS5B. This agent interacts directly with the viral polymerase and inhibits RNA synthesis in a manner noncompetitive with respect to GTP. Furthermore, in the absence of an in vitro-reconstituted HCV replicase assay employing viral and host proteins, the ability of compound 1 to inhibit NS5B-directed viral RNA replication was determined using the Huh7 cell-based HCV replicon system. Compound 1 reduced viral RNA in replicon cells with an IC(50) of approximately 0.5 microm, suggesting that the inhibitor was able to access the perinuclear membrane and inhibit the polymerase activity in the context of a replicase complex. Preliminary structure-activity studies on compound 1 led to the identification of a modified inhibitor, compound 4, showing an improvement in both biochemical and cell-based potency. Lastly, data are presented suggesting that these compounds interfere with the formation of negative and positive strand progeny RNA by a similar mode of action. Investigations are ongoing to assess the potential utility of such agents in the treatment of chronic HCV disease.
Journal of Biological Chemistry 11/2002; 277(41):38322-7. · 4.77 Impact Factor
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Kevin J Duffy,
Alan T Price,
Evelyne Delorme,
Susan B Dillon,
Celine Duquenne,
Connie Erickson-Miller,
Leslie Giampa,
Yifang Huang, Richard M Keenan,
Peter Lamb,
Nannan Liu,
Stephen G Miller,
Jon Rosen,
Anthony N Shaw,
Heather Smith,
Kenneth J Wiggall,
Lihua Zhang,
Juan I Luengo
[show abstract]
[hide abstract]
ABSTRACT: The invention of a new class of naphtho[1,2-d]imidazole thrombopoietin mimics based on a pharmacophore hypothesis for small-molecule thrombopoietic agonists is discussed. Parallel array synthesis and purification techniques allowed for the rapid exploration of structure-activity relationships within this class and for the improvement in TPO mimetic potencies and efficacies.
Journal of Medicinal Chemistry 09/2002; 45(17):3576-8. · 5.25 Impact Factor
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Kevin J Duffy,
Anthony N Shaw,
Evelyne Delorme,
Susan B Dillon,
Connie Erickson-Miller,
Leslie Giampa,
Yifang Huang, Richard M Keenan,
Peter Lamb,
Nannan Liu,
Stephen G Miller,
Alan T Price,
Jon Rosen,
Heather Smith,
Kenneth J Wiggall,
Lihua Zhang,
Juan I Luengo
[show abstract]
[hide abstract]
ABSTRACT: High-throughput screening has resulted in the discovery of thiosemicarbazone thrombopoietin mimics. A shared pharmacophore hypothesis between this series and a previously identified class, the pyrazol-4-ylidenehydrazines, led to the rapid optimization of both potency and efficacy of the thiosemicarbazones. The application of high-throughput chemistry and purification techniques allowed for the rapid elucidation of structure-activity relationships.
Journal of Medicinal Chemistry 09/2002; 45(17):3573-5. · 5.25 Impact Factor
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Kevin J. Duffy,
Michael G. Darcy,
Evelyne Delorme,
Susan B. Dillon,
Daniel F. Eppley,
Connie Erickson-Miller,
Leslie Giampa,
Christopher B. Hopson,
Yifang Huang, Richard M. Keenan, [......],
Jon Rosen,
Rakhi Shah,
Tony N. Shaw,
Heather Smith,
Kenneth C. Stark,
Shin-Shay Tian,
Curtis Tyree,
Kenneth J. Wiggall,
Lily Zhang,
Juan I. Luengo
[show abstract]
[hide abstract]
ABSTRACT: High-throughput screening for the induction of a luciferase reporter gene in a thrombopoietin (TPO)-responsive cell line resulted in the identification of 4-diazo-3-hydroxy-1-naphthalenesulfonic acids as TPO mimics. Modification of the core structure and adjustment of unwanted functionality resulted in the development of (5-oxo-1,5-dihydropyrazol-4-ylidene)hydrazines which exhibited efficacies equivalent to those of TPO in several cell-based assays designed to measure thrombopoietic activity. Furthermore, these compounds elicited biochemical responses in TPO-receptor-expressing cells similar to those in TPO itself, including kinase activation and protein phosphorylation. Potencies for the best compounds were high for such low molecular weight compounds (MW < 500) with EC50 values in the region of 1−20 nM.
09/2001;
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Bioorganic & Medicinal Chemistry Letters. 11(11):1441-1444.
