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137 results on '"Hutchinson, J. H."'

6. Pharmacokinetic and Pharmacodynamic Characterization of an Oral Lysophosphatidic Acid Type 1 Receptor-Selective Antagonist

Author

Swaney, J. S., primary, Chapman, C., additional, Correa, L. D., additional, Stebbins, K. J., additional, Broadhead, A. R., additional, Bain, G., additional, Santini, A. M., additional, Darlington, J., additional, King, C. D., additional, Baccei, C. S., additional, Lee, C., additional, Parr, T. A., additional, Roppe, J. R., additional, Seiders, T. J., additional, Ziff, J., additional, Prasit, P., additional, Hutchinson, J. H., additional, Evans, J. F., additional, and Lorrain, D. S., additional

Published
2010
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8. ChemInform Abstract: Substituted Thiopyrano(2,3,4-c,d)indoles as Potent, Selective, and Orally Active Inhibitors of 5-Lipoxygenase. Synthesis and Biological Evaluation of L-691,816.

Author

HUTCHINSON, J. H., primary, RIENDEAU, D., additional, BRIDEAU, C., additional, CHAN, C., additional, DELORME, D., additional, DENIS, D., additional, FALGUEYRET, J.-P., additional, FORTIN, R., additional, GUAY, J., additional, HAMEL, P., additional, JONES, T. R., additional, MACDONALD, D., additional, MCFARLANE, C. S., additional, PIECHUTA, H., additional, SCHEIGETZ, J., additional, TAGARI, P., additional, THERIEN, M., additional, and GIRARD, Y., additional

Published
2010
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11. ChemInform Abstract: Non‐Peptide Glycoprotein IIb/IIIa Antagonists. Part 11. Design and in vivo Evaluation of 3,4‐Dihydro‐1(1H)‐isoquinolinone‐Based Antagonists and Ethyl Ester Prodrugs.

Author

HUTCHINSON, J. H., primary, COOK, J. J., additional, BRASHEAR, K. M., additional, BRESLIN, M. J., additional, GLASS, J. D., additional, GOULD, R. J., additional, HALCZENKO, W., additional, HOLAHAN, M. A., additional, LYNCH, R. J., additional, SITKO, G. R., additional, STRANIERI, M. T., additional, and HARTMAN, G. D., additional

Published
1997
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12. ChemInform Abstract: Thiopyranol(2,3,4‐c,d)indoles as Inhibitors of 5‐Lipoxygenase, 5‐ Lipoxygenase‐Activating Protein, and Leukotriene C4 Synthase.

Author

HUTCHINSON, J. H., primary, CHARLESON, S., additional, EVANS, J. F., additional, FALGUEYRET, J.‐P., additional, HOOGSTEEN, K., additional, JONES, T. R., additional, KARGMAN, S., additional, MACDONALD, D., additional, MCFARLANE, C. S., additional, NICHOLSON, D. W., additional, PIECHUTA, H., additional, RIENDEAU, D., additional, SCHEIGETZ, J., additional, THERIEN, M., additional, and GIRARD, Y., additional

Published
1996
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13. ChemInform Abstract: Thiopyrano(2,3,4‐cd)indoles as 5‐Lipoxygenase Inhibitors: Synthesis, Biological Profile, and Resolution of 2‐(2‐(1‐(4‐Chlorobenzyl)‐4‐ methyl‐6‐((5‐phenylpyridin‐2‐yl)methoxy)‐4,5‐dihydro‐1H‐thiopyrano(2,3, 4‐cd)indol‐2‐yl)ethoxy)butanoic Acid.

Author

HUTCHINSON, J. H., primary, RIENDEAU, D., additional, BRIDEAU, C., additional, CHAN, C., additional, FALGUEYRET, J.‐P., additional, GUAY, J., additional, JONES, T. R., additional, LEPINE, C., additional, MACDONALD, D., additional, MCFARLANE, C. S., additional, PIECHUTA, H., additional, SCHEIGETZ, J., additional, TAGARI, P., additional, THERIEN, M., additional, and GIRARD, Y., additional

Published
1994
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14. Thiopyrano[2,3,4-cd]indoles as 5-Lipoxygenase Inhibitors: Synthesis, Biological Profile, and Resolution of 2-[2-[1-(4-Chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano[2,3,4-cd]indol-2-yl]ethoxy]butanoic Acid

Author

Hutchinson, J. H., primary, Riendeau, D., additional, Brideau, C., additional, Chan, C., additional, Falgueyret, J.-P., additional, Guay, J., additional, Jones, T. R., additional, Lepine, C., additional, and Macdonald, D., additional

Published
1994
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17. Pharmacology of MK-0591 (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-yl-methoxy)-indol-2-yl]-2,2-dimethyl propanoic acid), a potent, orally active leukotriene biosynthesis inhibitor

Author

Brideau, C., primary, Chan, C., additional, Charleson, S., additional, Denis, D., additional, Evans, J. F., additional, Ford-Hutchinson, A. W., additional, Fortin, R., additional, Gillard, J. W., additional, Guay, J., additional, Guévremont, D., additional, Hutchinson, J. H., additional, Jones, T. R., additional, Leger, S., additional, Mancini, J. A., additional, McFarlane, C. S., additional, Pickett, C., additional, Piechuta, H., additional, Prasit, P., additional, Riendeau, D., additional, Rouzer, C. A., additional, Tagari, P., additional, Vickers, P. J., additional, Young, R. N., additional, and Abraham, W. M., additional

Published
1992
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22. Disposition of a novel and potent α v β 3 antagonist in animals, and extrapolation to man.

Author

Prueksaritanont, T., Fernandez-Metzler, C., Meng, Y., Barrish, A., Halczenko, W., Rodan, S. B., Hutchinson, J. H., Duggan, M. E., and Lin, J. H.

Subjects
OSTEOPOROSIS, DISEASES in women, MENOPAUSE, BONE densitometry, OSTEOCLASTS, BONE cells
Abstract

1. The disposition of 3-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) propyl]-imidazolidin-1-yl}-3(S)-(6-methoxy-pyridin-3-yl)propionic acid (compound A), a potent and selective α v β 3 antagonist, was characterized in several animal species in support of its selection for preclinical safety studies and potential clinical development. 2. Compound A exhibited marked species differences in pharmacokinetics; the plasma clearances and bioavailabilities ranged from 33-47 ml min -1 kg -1 in rats and mice to 4-9 ml min -1 kg -1 in dogs and monkeys, and about 20% in rats to 70-80% in dogs and monkeys, respectively. Both the intravenous (i.v.) and oral kinetics of compound A were linear over the dose range studied in dogs (0.1-5 mg kg -1 i.v. and 0.25-20 mg kg -1 orally [p.o.]) and rats (1-30 mg kg -1 i.v. and 4-160 mg kg -1 p.o.). 3. Compound A was eliminated substantially by urinary excretion; the urinary recovery of the unchanged drug was 67% in rhesus, 48% in dogs and about 30% in rats. In these animal species, biotransformation was modest. 4. Following i.v. administration of [ 14 C]-compound A to rats, the radioactivity rapidly distributed to all tissues investigated, with high levels of the radioactivity detected in liver, kidney and intestine soon after the drug administration. The radioactivity declined rapidly, with less than 1% of the i.v. dose remaining at 30-h post-dose. 5. Compound A was moderately bound to plasma proteins, with unbound fractions of 26, 20, 14 and 5% for rats, dogs, monkeys and humans, respectively. It was bound primarily to human α 1 -acid glycoprotein (about 85% binding at 0.1% concentration), as compared with human albumin (< 50% binding at 4% concentration). 6. Using simple allometry, compound A was predicted to exhibit relatively low clearance (1-3 ml min -1 kg -1 ) and low volume of distribution (0.1-0.3 l kg -1 ) in humans. Based on the predicted values, compound A was projected to exhibit a favourable oral pharmacokinetic profile in humans, with good bioavailability (50-80%). These predicted values provided a basis for compound selection for further development. [ABSTRACT FROM AUTHOR]

Published
2004
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23. Pharmacokinetic and pharmacodynamic characterization of an oral lysophosphatidic Acid type 1 receptor-selective antagonist.

Author

Swaney, J S, Chapman, C, Correa, L D, Stebbins, K J, Broadhead, A R, Bain, G, Santini, A M, Darlington, J, King, C D, Baccei, C S, Lee, C, Parr, T A, Roppe, J R, Seiders, T J, Ziff, J, Prasit, P, Hutchinson, J H, Evans, J F, and Lorrain, D S

Abstract

Lysophosphatidic acid (LPA) is a bioactive phospholipid that signals through a family of at least six G protein-coupled receptors designated LPA(1-6). LPA type 1 receptor (LPA(1)) exhibits widespread tissue distribution and regulates a variety of physiological and pathological cellular functions. Here, we evaluated the in vitro pharmacology, pharmacokinetic, and pharmacodynamic properties of the LPA(1)-selective antagonist AM095 (sodium, {4'-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-acetate) and assessed the effects of AM095 in rodent models of lung and kidney fibrosis and dermal wound healing. In vitro, AM095 was a potent LPA(1) receptor antagonist because it inhibited GTPγS binding to Chinese hamster ovary (CHO) cell membranes overexpressing recombinant human or mouse LPA(1) with IC(50) values of 0.98 and 0.73 μM, respectively, and exhibited no LPA(1) agonism. In functional assays, AM095 inhibited LPA-driven chemotaxis of CHO cells overexpressing mouse LPA(1) (IC(50) = 778 nM) and human A2058 melanoma cells (IC(50) = 233 nM). In vivo, we demonstrated that AM095: 1) had high oral bioavailability and a moderate half-life and was well tolerated at the doses tested in rats and dogs after oral and intravenous dosing, 2) dose-dependently reduced LPA-stimulated histamine release, 3) attenuated bleomycin-induced increases in collagen, protein, and inflammatory cell infiltration in bronchalveolar lavage fluid, and 4) decreased kidney fibrosis in a mouse unilateral ureteral obstruction model. Despite its antifibrotic activity, AM095 had no effect on normal wound healing after incisional and excisional wounding in rats. These data demonstrate that AM095 is an LPA(1) receptor antagonist with good oral exposure and antifibrotic activity in rodent models.

Published
2011
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25. Nonpeptide α<INF>v</INF>β<INF>3</INF> Antagonists. Part 11:  Discovery and Preclinical Evaluation of Potent α<INF>v</INF>β<INF>3</INF> Antagonists for the Prevention and Treatment of Osteoporosis

Author

Coleman, P. J., Brashear, K. M., Askew, B. C., Hutchinson, J. H., McVean, C. A., Duong, L. T., Feuston, B. P., Fernandez-Metzler, C., Gentile, M. A., Hartman, G. D., Kimmel, D. B., Leu, C.-T., Lipfert, L., Merkle, K., Pennypacker, B., Prueksaritanont, T., Rodan, G. A., Wesolowski, G. A., Rodan, S. B., and Duggan, M. E.

Abstract

3-(S)-Pyrimidin-5-yl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5e) and 3-(S)-(methylpyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5f) were identified as potent and selective antagonists of the αvβ3 receptor. These compounds have excellent in vitro profiles (IC50 = 0.07 and 0.08 nM, respectively), significant unbound fractions in human plasma (6 and 4%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in an in vivo model of bone turnover following once-daily oral administration, these two compounds were selected for clinical development for the treatment of osteoporosis.

Published
2004

26. Familial renal dwarfism.

Author

GRAHAM, STANLEY, HUTCHINSON, JAMES HOLMES, Graham, S, and Hutchinson, J H

Published
1941

28. Nonpeptide α<INF>v</INF>β<INF>3</INF> Antagonists. 8. In Vitro and in Vivo Evaluation of a Potent α<INF>v</INF>β<INF>3</INF> Antagonist for the Prevention and Treatment of Osteoporosis

Author

Hutchinson, J. H., Halczenko, W., Brashear, K. M., Breslin, M. J., Coleman, P. J., Duong, L. T., Fernandez-Metzler, C., Gentile, M. A., Fisher, J. E., Hartman, G. D., Huff, J. R., Kimmel, D. B., Leu, C.-T., Meissner, R. S., Merkle, K., Nagy, R., Pennypacker, B., Perkins, J. J., Prueksaritanont, T., Rodan, G. A., Varga, S. L., Wesolowski, G. A., Zartman, A. E., Rodan, S. B., and Duggan, M. E.

Abstract

3(S)-(6-Methoxypyridin-3-yl)-3-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)propyl]imidazolidin-1-yl}propionic acid 6 was identified as a potent and selective antagonist of the αvβ3 receptor. This compound has an excellent in vitro profile (IC50 = 0.08 nM), a significant unbound fraction in human plasma (12%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in three in vivo models of bone turnover, the compound was selected for clinical development. To support the ongoing metabolism and safety studies, a novel strategy was employed in which a series of oxidized derivatives of 6 were prepared by exposure of 6 (or the methyl ester) to chemical oxidizing agents. These products proved useful in the identification of active metabolites generated by either in vitro or in vivo metabolism.

Published
2003

33. N-Arylpiperazinone Inhibitors of Farnesyltransferase:  Discovery and Biological Activity

Author

Williams, T. M., Bergman, J. M., Brashear, K., Breslin, M. J., Dinsmore, C. J., Hutchinson, J. H., MacTough, S. C., Stump, C. A., Wei, D. D., Zartman, C. B., Bogusky, M. J., Culberson, J. C., Buser-Doepner, C., Davide, J., Greenberg, I. B., Hamilton, K. A., Koblan, K. S., Kohl, N. E., Liu, D., Lobell, R. B., Mosser, S. D., O'Neill, T. J., Rands, E., Schaber, M. D., Wilson, F., Senderak, E., Motzel, S. L., Gibbs, J. B., Graham, S. L., Heimbrook, D. C., Hartman, G. D., Oliff, A. I., and Huff, J. R.

Published
1999

35. Non-Peptide Glycoprotein IIb/IIIa Antagonists. 11. Design and in Vivo Evaluation of 3,4-Dihydro-1(1H)-isoquinolinone-Based Antagonists and Ethyl Ester Prodrugs

Author

Hutchinson, J. H., Cook, J. J., Brashear, K. M., Breslin, M. J., Glass, J. D., Gould, R. J., Halczenko, W., Holahan, M. A., Lynch, R. J., Sitko, G. R., Stranieri, M. T., and Hartman, G. D.

Abstract

The structure−activity relationship of a series of orally active glycoprotein IIb/IIIa antagonists containing a nitrogen heterocycle grafted onto a 3,4-dihydro-1(1H)-isoquinolinone core is described. These compounds are structurally novel analogs of the progenitor compound 1 (L-734,217, [[3(R)-[2-(piperidin-4-yl)ethyl]-2-oxopiperidinyl]acetyl]-3(R)-methyl-β-alanine) in which the lactam chiral center has been removed. The 4-piperazinyl- and 4-piperidinyl-substituted 3,4-dihydro-1(1H)-isoquinolinones were found to be optimal for in vitro potency. In addition, substitution at the 3-position of the β-amino acid enhanced potency with the 3-pyridyl and 3-ethynyl analogs being the most potent prepared. Attempts to improve the in vivo profile of these compounds focused on modification of the physical properties. Ester prodrugs were prepared to increase the lipophilicity and remove the zwitterionic nature of the antagonists. The prodrug approach, coupled with the arylpiperazine terminus (pKa = ~9.0), afforded moderately basic and relatively nonpolar compounds. The acid N-[[7-(piperazin-1-yl)-3,4-dihydro-1(1H)-oxoisoquinolin-2-yl]acetyl]-3(S)-ethynyl-β-alanine, 6d (L-767,679), is a potent fibrinogen receptor antagonist able to inhibit the ADP-induced aggregation of human gel-filtered platelets with an IC50 of 12 nM. Although 6d is orally active based on the results of an ex vivo dog assay at 0.3 mg/kg, the ethyl ester prodrug of this compound, 19 (L-767,685), is better absorbed at this dose than 6d. Upon oral dosing, the ester 19 is converted to 6d in vivo in dog with an estimated oral systemic availability of >17% (0−8 h, AUC19po/AUC6div). In addition, studies in monkey at an oral dose of 1 mg/kg show that 19 affects the complete inhibition of the ex vivo platelet aggregation in response to ADP between 2 and 8 h postdose with the level of inhibition remaining at 40% at 12 h postdose. This level of activity was superior to that observed for 6d and 1 at the same dose. Using ex vivo ADP-induced aggregation data from rhesus monkey (n = 2, 0−8 h using the AUC19po/AUC6div), the estimated systemic oral availability of 6d when dosed as 19 is 32%.

Published
1996

38. Copper deficiency in a low birthweight infant.

Author

Yuen, P, Lin, H J, and Hutchinson, J H

Abstract

Copper deficiency is reported in an infant of very low birthweight. It was characterised by extensive bone changes, severe neutropenia, and hypocupraemia. These manifestations could have been missed but for an intercurrent pneumonia which led to an x-ray of the chest. [ABSTRACT FROM AUTHOR]

Published
1979

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