John T. Shirley
Pfizer
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Featured researches published by John T. Shirley.
Bioorganic & Medicinal Chemistry Letters | 1995
John B. Cheng; Kelvin Cooper; Allen J. Duplantier; James Frederick Eggler; Kenneth G. Kraus; Sally C. Marshall; Anthony Marfat; Hiroko Masamune; John T. Shirley; Jeenene E. Tickner; John P. Umland
Abstract The synthesis and biological properties of a novel series of potent and selective phosphodiesterase type IV (PDE IV) inhibitors are described. These catechol benzimidazoles were designed from rolipram and initial compounds reflected a similarly high affinity for the [ 3 H]rolipram b binding site (500 to 1000X greater affinity for the [ 3 H]rolipram binding site over the PDE IV inhibitory site). However, SAR studies on the 3-alkoxy position revealed that this [ 3 H]rolipram binding site affinity could be attenuated, while potentiating the PDE IV inhibitory activity. This resulted in the 2-indanyl analog 13 which is a potent, selective PDE IV inhibitor with a 15X differential in favor of PDE IV binding.
Bioorganic & Medicinal Chemistry Letters | 1995
Hiroko Masamune; John B. Cheng; Kelvin Cooper; James F. Eggier; Anthony Marfat; Sally C. Marshall; John T. Shirley; Jeanene E. Tickner; John P. Umland; Enrique Vazquez
Abstract The synthesis and the in vitro properties of a novel series of potent and selective phosphodiesterase type IV (PDE IV) inhibitors is described. Despite bearing structural similarity to rolipram, several of these compounds have much reduced affinity for the [3H]rolipram binding site.
Bioorganic & Medicinal Chemistry Letters | 1997
Robert J. Chambers; Anthony Marfat; John B. Cheng; V.L. Cohan; David B. Damon; Allen J. Duplantier; T.A. Hibbs; Teresa H. Jenkinson; K.L. Johnson; Kenneth G. Kraus; E.R. Pettipher; E.D. Salter; John T. Shirley; John P. Umland
Abstract Tumor necrosis factor-α (TNF-α) has been implicated as a key mediator in the progression of rheumatoid arthritis. Inhibitors of phosphodiesterase IV (PDE IV) have been shown to inhibit the production of TNF-α by elevating intracellular levels of cyclic adenosine monophosphate (cAMP). Our efforts in a series of biarylcarboxamides have led to the identification of 8j (CP-353,164) as a potent inhibitor of PDE IV and TNF-α production.
Bioorganic & Medicinal Chemistry Letters | 1998
Robert J. Chambers; G.W. Antognoli; John B. Cheng; Anthony Marfat; J.S. Pillar; John T. Shirley; J.W. Watson
By addressing the issues of potency and metabolism in 3, a new series of LTD4 antagonists represented by (+)-26 was developed which is equipotent to clinical LTD4 antagonists Zafirlukast (1) and Pranlukast (2).
Bioorganic & Medicinal Chemistry Letters | 1999
Robert J. Chambers; Anthony Marfat; G.W. Antognoli; John B. Cheng; David B. Damon; Alexander V. Kuperman; T.C. Liston; C. Mebus; J.S. Pillar; John T. Shirley; J.W. Watson
CP-199,330 (3) and CP-199,331 (4) are cysLT1 receptor antagonists that are equipotent to marketed cysLT1 receptor antagonists zafirlukast and pranlukast, show good pharmacokinetics in rats and monkeys, and are devoid of liver toxicity in monkeys as seen in CP-85,958 (1).
Bioorganic & Medicinal Chemistry Letters | 1995
E.G. Andrews; G.W. Antognoli; R. Breslow; M.P. Carta; Thomas J. Carty; Robert J. Chambers; John B. Cheng; V.L. Cohan; Judith L. Collins; David B. Damon; J. Delehunt; James Frederick Eggler; James D. Eskra; K.W. Freiert; William A. Hada; Anthony Marfat; Hiroko Masamune; L.S. Melvin; Christian J. Mularski; B.A. Naclerio; C.J. Pazoles; J.S. Pillar; L.A. Rappach; P. Reiche; Frank W. Rusek; H. Sherman; John T. Shirley; Francis J. Sweeney; Jeanene E. Tickner; J.W. Watson
Abstract The development of two novel LTD 4 receptor antagonists as clinical candidates for the treatment of asthma is described. The first generation compound, CP-80,798, was found to be a balanced 5-lipoxygenase inhibitor (5-LOI)/LTD 4 antagonist (LTD 4 -A), while the second generation compound, CP-85,958, is a selective LTD 4 antagonist.
Bioorganic & Medicinal Chemistry Letters | 1998
Robert J. Chambers; G.W. Antognoli; John B. Cheng; Alexander V. Kuperman; T.C. Liston; Anthony Marfat; Brian S. Owens; J.S. Pillar; John T. Shirley; J.W. Watson
A new series of cysLT1 receptor antagonists represented by CP-288,886 (7) and CP-265,298 (8) were developed which are equipotent to clinical cysLT1 receptor antagonists Zafirlukast (1) and Pranlukast (2).
Bioorganic & Medicinal Chemistry Letters | 1995
Hiroko Masamune; R. Breslow; John B. Cheng; Maryrose J. Conklyn; James Frederick Eggler; Anthony Marfat; L.S. Melvin; J.S. Pillar; John T. Shirley; Henry J. Showell; Jeanene E. Tickner
Abstract The development of novel LTB 4 antagonists from a class of quinolylmethyl LTD 4 antagonists is described. These α-methyl quinolylmethyl chromanols were found to have good vitro activity.
Bioorganic & Medicinal Chemistry Letters | 1998
Matthew Frank Brown; Anthony Marfat; Gerard Antognoli; Robert J. Chambers; John B. Cheng; David B. Damon; Theodore E. Liston; Molly A. McGlynn; Stacie P. O'Sullivan; Brian S. Owens; J.S. Pillar; John T. Shirley; John W. Watson
Exploration of the indole nitrogen region of Zafirlukast (1) has uncovered a potent series of cysteinyl leukotriene D4 (LTD4) antagonists. These studies showed that a variety of functionality could be incorporated in this region of the molecule without sacrificing potency. Efforts to exploit this site in order to improve oral efficacy are discussed.
Bioorganic & Medicinal Chemistry Letters | 1995
Hiroko Masamune; James Frederick Eggler; Anthony Marfat; Lawrence S. Melvin; Frank W. Rusek; Jeanene E. Tickner; John B. Cheng; John T. Shirley
Abstract A series of pyridine chromanols were synthesized and evaluated as LTD 4 -antagonists (LTD 4 -A). The quinoline sidechain of this class of such agents, as exemplified by REV-5901, has until now been deemed as essential for potent activity. However, by manipulating substituents on a pyridine ring, quinoline-like potency can be achieved. The results indicate that this is a function of pKa.