Michael P. Clay
Eli Lilly and Company
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Featured researches published by Michael P. Clay.
Tetrahedron | 1999
Miles Goodman Siegel; Michael O. Chaney; Robert F. Bruns; Michael P. Clay; Douglas A. Schober; Anne M. Van Abbema; Douglas W. Johnson; Buddy E. Cantrell; Patric James Hahn; David C. Hunden; Donald R. Gehlert; Hamideh Zarrinmayeh; Paul L. Ornstein; Dennis M. Zimmerman; Gary A. Koppel
Abstract This study describes the integrated application of parallel synthesis and computational chemistry to the design of potent nonpeptide antagonists for the neuropeptide Y-1 (NPY1) receptor. A lead molecule was modeled in the active site of the NPY1 receptor, and a potentially fruitful region for analog construction was identified. Synthesis of suitable scaffolds followed by solution phase generation of a small library of analogs produced a compound with 5-fold improvement in binding over the already potent lead. This new compound was shown to be an unanticipated side product of the parallel synthesis reaction.
Journal of Cardiovascular Pharmacology | 1992
Paul J. Simpson; Judith A. Schelm; Jeffrey K. Smallwood; Michael P. Clay; Terry D. Lindstrom
Summary: The purpose of this study was to determine whether the selective type IV cAMP-phosphodiesterase inhibitor rolipram could reduce the reperfusion injury that occurs during myocardial infarction in the anesthetized dog. This question was tested in pentobarbital-anesthetized dogs subject to 90 min of regional myocardial ischemia and 5 h of reperfusion. Dogs were treated with 1 mg/kg of rolipram (i.v., 15 min before reperfusion) followed by a 1 mg/kg/h infusion over the duration of the 5 h of reperfusion. Rolipram was tested in vitro for efficacy in inhibition of isolated human neutrophil superoxide generation. Rolipram produced significant inhibition of superoxide production over the concentration range of 0.1–100 μM- rolipram when neutrophils were stimulated with a 10 -7 M concentration of the chemotactic peptide f-Met-Leu-Phe. Rolipram significantly inhibited superoxide generation from human and canine granulocytes in whole blood stimulated by zymosan. Therapeutic concentrations of rolipram in the blood of dogs were achieved during the course of the experiments with a plasma concentration of 0.761 ± 0.095 μg/ml (2.76 ± 0.34 μ- M) at the time of reperfusion, and 0.574 ± 0.098 μg/ml (2.08 ± 0.36 μ M) at the end of the reperfusion period. The relative severity of myocardial ischemia between the two treatment groups was similar as assessed with radiolabeled microsphere measurement of myocardial blood flow. Transmural myocardial blood flows were not significantly different between the two groups after coronary occlusion (control, 0.05 ± 0.01 ml/min/g, n = 6, vs. rolipram, 0.18 ± 0.07 ml/min/g, n = 6; p = 0.48). There was not a significant reduction in the accumulation of neutrophils in the myocardium as assessed by the marker enzyme myeloperoxidase (control, 2.33 ± 1.07 U/g, n = 5, vs. rolipram, 0.54 ± 0.28 U/g, n = 6; p = 0.0548). Myocardial infarct size determined postmortem was not limited by rolipram treatment (control, 31.1 ± 2.6% infarct/ area at risk, n = 6, vs. rolipram, 23.3 ± 7.8% infarct/area at risk, n = 6; p > 0.05). Even though rolipram did not result in statistically significant protection as measured by infarct size, there was a significant attenuation of the “no-reflow” phenomenon with rolipram treatment. Circumflex coronary blood flow declines that were evident in the vehicle-treated group did not occur in the rolipram treatment group. These data indicate that cAMP-phosphodiesterase inhibition with rolipram is not sufficient to provide protection against myocardial reperfusion injury.
Chirality | 1999
Michael P. Clay; Brenda R. Hanssen; Sekhar S. Surapaneni; Terry D. Lindstrom
Incubation of (R)-tazofelone and (S)-tazofelone in rat, dog, and human liver microsomes demonstrated that the (R)-tazofelone enantiomer was more rapidly metabolized, with two diastereomeric sulfoxides as the major metabolites formed in all three species. The two diasteresomers epimerized at physiological pH, therefore total sulfoxide formation rates were measured. The formation of the total sulfoxide metabolites followed Michaelis-Menten kinetics. The K(m), Vmax, and intrinsic formation clearance (Vmax/K(m)) values were determined in rat, dog, and human liver microsomes. The intrinsic formation clearance of sulfoxide from (R)-tazofelone exceeded that of (S)-tazofelone in all three species. In vivo studies in rats and dogs dosed orally and intravenously confirmed the stereoselective metabolism of tazofelone observed in vitro. Plasma concentrations of (S)-tazofelone exceeded (R)-tazofelone in rats and dogs by a factor of 3 to 4. In rat portal plasma, both enantiomers were of approximately equal concentration after oral dosing, indicating similar absorption. The half-lives of tazofelone and total sulfoxides in rats were 3.5 and 2.8 h, respectively. In dogs, the half-lives of tazofelone and total sulfoxides were 2.2 and 5.5 h, respectively. Plasma clearance was 2.3 l/h in rats and 1.4 l/h in dogs, and the volumes of distribution were 12 and 4.5 l, respectively, in rats and dogs. Both enantiomers were highly bound to plasma proteins to a similar extent in both species.
Pharmacology, Biochemistry and Behavior | 2001
Fengju Bai; Xia Li; Michael P. Clay; Terry D. Lindstrom; Phil Skolnick
Neuropharmacology | 2001
Xia Li; Joseph P. Tizzano; Kelly I. Griffey; Michael P. Clay; Terry D. Lindstrom; Phil Skolnick
Journal of Medicinal Chemistry | 2004
Thomas A. Engler; James Robert Henry; Sushant Malhotra; Brian Eugene Cunningham; Kelly Wayne Furness; Joseph T. Brozinick; Timothy Paul Burkholder; Michael P. Clay; Joshua Ryan Clayton; Clive Gideon Diefenbacher; Eric Hawkins; Philip W. Iversen; Yihong Li; Terry D. Lindstrom; Angela Lynn Marquart; Johnathan Alexander Mclean; David Mendel; Elizabeth A. Misener; Daniel A. Briere; John O'Toole; Warren J. Porter; Steven Queener; Jon K. Reel; Rebecca A. Owens; Richard A. Brier; Thomas E. Eessalu; Jill R. Wagner; and Robert M. Campbell; Renee Vaughn
Journal of Medicinal Chemistry | 2004
Timothy I. Richardson; Paul L. Ornstein; Karin Briner; Matthew Joseph Fisher; Ryan T. Backer; C. Kelly Biggers; Michael P. Clay; Paul J. Emmerson; Larry Wayne Hertel; Hansen M. Hsiung; Saba Husain; Steven D. Kahl; Jonathan A. Lee; Terry D. Lindstrom; Michael J. Martinelli; John P. Mayer; Jeffery T. Mullaney; Thomas P. O'brien; Joseph Matthew Pawlak; Kevin D. Revell; Jikesh Shah; John M. Zgombick; R. Jason Herr; Alex Melekhov; Peter B. Sampson; Chi-Hsin R. King
Journal of Medicinal Chemistry | 2005
Ana B. Bueno; Ivan Collado; Alfonso de Dios; Carmen Dominguez; Jose Alfredo Martin; Luisa M. Martín; Maria Angeles Martinez-Grau; Carlos Montero; Concepcion Pedregal; John T. Catlow; D. Scott Coffey; Michael P. Clay; Anne H. Dantzig; Terry D. Lindstrom; James A. Monn; Haiyan Jiang; Darryle D. Schoepp; Robert E. Stratford; Linda B. Tabas; Joseph P. Tizzano; and Rebecca A. Wright; M. Herin
Bioorganic & Medicinal Chemistry | 2007
Christophe Guillon; Gary A. Koppel; Michael J. Brownstein; Michael O. Chaney; Craig F. Ferris; Shi-fang Lu; Karine Fabio; Marvin J. Miller; Ned D. Heindel; David C. Hunden; Robin D. G. Cooper; Stephen W. Kaldor; Jeffrey J. Skelton; Bruce A. Dressman; Michael P. Clay; Mitchell I. Steinberg; Robert F. Bruns; Neal G. Simon
Cns Drug Reviews | 2006
Michael J. O'Neill; Tracey K. Murray; Michael P. Clay; Terry D. Lindstrom; Charles R. Yang; Eric S. Nisenbaum