John F. Fay
United States Military Academy
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Featured researches published by John F. Fay.
Antimicrobial Agents and Chemotherapy | 2004
David B. Olsen; Anne B. Eldrup; Linda Bartholomew; Balkrishen Bhat; Michele Bosserman; Alessandra Ceccacci; Lawrence F. Colwell; John F. Fay; Osvaldo A. Flores; Krista Getty; Jay A. Grobler; Robert L. Lafemina; Eric J. Markel; Giovanni Migliaccio; Marija Prhavc; Mark Stahlhut; Joanne E. Tomassini; Malcolm Maccoss; Daria J. Hazuda; Steven S. Carroll
ABSTRACT Improved treatments for chronic hepatitis C virus (HCV) infection are needed due to the suboptimal response rates and deleterious side effects associated with current treatment options. The triphosphates of 2′-C-methyl-adenosine and 2′-C-methyl-guanosine were previously shown to be potent inhibitors of the HCV RNA-dependent RNA polymerase (RdRp) that is responsible for the replication of viral RNA in cells. Here we demonstrate that the inclusion of a 7-deaza modification in a series of purine nucleoside triphosphates results in an increase in inhibitory potency against the HCV RdRp and improved pharmacokinetic properties. Notably, incorporation of the 7-deaza modification into 2′-C-methyl-adenosine results in an inhibitor with a 20-fold-increased potency as the 5′-triphosphate in HCV RdRp assays while maintaining the inhibitory potency of the nucleoside in the bicistronic HCV replicon and with reduced cellular toxicity. In contrast, while 7-deaza-2′-C-methyl-GTP also displays enhanced inhibitory potency in enzyme assays, due to poor cellular penetration and/or metabolism, the nucleoside does not inhibit replication of a bicistronic HCV replicon in cell culture. 7-Deaza-2′-C-methyl-adenosine displays promising in vivo pharmacokinetics in three animal species, as well as an acute oral lethal dose in excess of 2,000 mg/kg of body weight in mice. Taken together, these data demonstrate that 7-deaza-2′-C-methyl-adenosine is an attractive candidate for further investigation as a potential treatment for HCV infection.
Journal of Pharmacology and Experimental Therapeutics | 2007
Christopher A. Salvatore; James C. Hershey; Halea A. Corcoran; John F. Fay; Victor K. Johnston; Eric L. Moore; Scott D. Mosser; Christopher S. Burgey; Daniel V. Paone; Anthony W. Shaw; Samuel Graham; Joseph P. Vacca; Theresa M. Williams; Kenneth S. Koblan; Stefanie A. Kane
Calcitonin gene-related peptide (CGRP) is a potent neuropeptide that plays a key role in the pathophysiology of migraine headache. CGRP levels in the cranial circulation are increased during a migraine attack, and CGRP itself has been shown to trigger migraine-like headache. The correlation between CGRP release and migraine headache points to the potential utility of CGRP receptor antagonists as novel therapeutics in the treatment of migraine. Indeed, clinical proof-of-concept in the acute treatment of migraine was demonstrated with an intravenous formulation of the CGRP receptor antagonist BIBN4096BS (olcegepant). Here we report on the pharmacological characterization of the first orally bioavailable CGRP receptor antagonist in clinical development, MK-0974 [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide]. In vitro, MK-0974 is a potent antagonist of the human (Ki = 0.77 nM) and rhesus (Ki = 1.2 nM) CGRP receptors but displays >1500-fold lower affinity for the canine and rat receptors as determined via 125I-human CGRP competition binding assays. A rhesus pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging was utilized to determine the in vivo activity of CGRP receptor antagonism. MK-0974 produced a concentration-dependent inhibition of dermal vasodilation, generated by capsaicin-induced release of endogenous CGRP, with plasma concentrations of 127 and 994 nM required to block 50 and 90% of the blood flow increase, respectively. In conclusion, MK-0974 is a highly potent, selective, and orally bioavailable CGRP receptor antagonist, which may be valuable in the acute treatment of migraine.
Journal of Pharmacology and Experimental Therapeutics | 2010
Christopher A. Salvatore; Eric L. Moore; Amy Calamari; Jacquelynn J. Cook; Maria S. Michener; Stacey O'Malley; Patricia Miller; Cyrille Sur; David L. Williams; Zhizhen Zeng; Andrew Danziger; Joseph J. Lynch; Christopher P. Regan; John F. Fay; Yui S. Tang; Chi-Chung Li; Nicole T. Pudvah; Rebecca B. White; Ian M. Bell; Steven N. Gallicchio; Samuel Graham; Harold G. Selnick; Joseph P. Vacca; Stefanie A. Kane
Calcitonin gene-related peptide (CGRP) has long been hypothesized to play a key role in migraine pathophysiology, and the advent of small-molecule antagonists has clearly demonstrated a clinical link between blocking the CGRP receptor and migraine efficacy. 2-[(8R)-8-(3,5-Difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (MK-3207) represents the third CGRP receptor antagonist to display clinical efficacy in migraine trials. Here, we report the pharmacological characterization of MK-3207, a potent and orally bioavailable CGRP receptor antagonist. In vitro, MK-3207 is a potent antagonist of the human and rhesus monkey CGRP receptors (Ki = 0.024 nM). In common with other CGRP receptor antagonists, MK-3207 displays lower affinity for CGRP receptors from other species, including canine and rodent. As a consequence of species selectivity, the in vivo potency was assessed in a rhesus monkey pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging. MK-3207 produced a concentration-dependent inhibition of dermal vasodilation, with plasma concentrations of 0.8 and 7 nM required to block 50 and 90% of the blood flow increase, respectively. The tritiated analog [3H]MK-3207 was used to study the binding characteristics on the human CGRP receptor. [3H]MK-3207 displayed reversible and saturable binding (KD = 0.06 nM), and the off-rate was determined to be 0.012 min−1, with a t1/2 value of 59 min. In vitro autoradiography studies on rhesus monkey brain slices identified the highest level of binding in the cerebellum, brainstem, and meninges. Finally, as an index of central nervous system penetrability, the in vivo cerebrospinal fluid/plasma ratio was determined to be 2 to 3% in cisterna magna-ported rhesus monkeys.
ACS Chemical Neuroscience | 2011
Mark E. Layton; Michael J. Kelly; Kevin J. Rodzinak; Philip E. Sanderson; Steven D. Young; Rodney A. Bednar; Anthony G. DiLella; Terrence P. McDonald; Hao Wang; Scott D. Mosser; John F. Fay; Michael E. Cunningham; Duane R. Reiss; Christine Fandozzi; Nicole Trainor; Annie Liang; Edward V. Lis; Guy R. Seabrook; Mark O. Urban; James A. Yergey; Kenneth S. Koblan
A series of 3-substituted aminocyclopentanes has been identified as highly potent and selective NR2B receptor antagonists. Incorporation of a 1,2,4-oxadiazole linker and substitution of the pendant phenyl ring led to the discovery of orally bioavailable analogues that showed efficient NR2B receptor occupancy in rats. Unlike nonselective NMDA antagonists, the NR2B-selective antagonist 22 showed no adverse affects on motor coordination in the rotarod assay at high dose. Compound 22 was efficacious following oral administration in a spinal nerve ligation model of neuropathic pain and in an acute model of Parkinsons disease in a dose dependent manner.
Bioorganic & Medicinal Chemistry Letters | 2009
Ian M. Bell; Rodney A. Bednar; Halea A. Corcoran; John F. Fay; Steven N. Gallicchio; Victor K. Johnston; James C. Hershey; Cynthia Miller-Stein; Eric L. Moore; Scott D. Mosser; Shane Roller; Christopher A. Salvatore; Cory R. Theberge; Bradley K. Wong; C. Blair Zartman; Stefanie A. Kane; Theresa M. Williams; Samuel L. Graham; Joseph P. Vacca
A series of tricyclic CGRP receptor antagonists was optimized in order to improve oral bioavailability. Attenuation of polar surface area and incorporation of a weakly basic indoline nitrogen led to compound 5, a potent antagonist with good oral bioavailability in three species.
ACS Medicinal Chemistry Letters | 2016
Christopher James Bungard; Peter D. Williams; Jeanine Ballard; David Jonathan Bennett; Christian Beaulieu; Carolyn Bahnck-Teets; Steve Carroll; Ronald K. Chang; David C. Dubost; John F. Fay; Tracy L. Diamond; Thomas J. Greshock; Li Hao; M. Katharine Holloway; Peter J. Felock; Jennifer J. Gesell; Hua-Poo Su; Jesse J. Manikowski; Daniel J. McKay; Mike Miller; Xu Min; Carmela Molinaro; Oscar M. Moradei; Philippe G. Nantermet; Christian Nadeau; Rosa I. Sanchez; Tummanapalli Satyanarayana; William D. Shipe; Sanjay K. Singh; Vouy Linh Truong
A novel HIV protease inhibitor was designed using a morpholine core as the aspartate binding group. Analysis of the crystal structure of the initial lead bound to HIV protease enabled optimization of enzyme potency and antiviral activity. This afforded a series of potent orally bioavailable inhibitors of which MK-8718 was identified as a compound with a favorable overall profile.
Bioorganic & Medicinal Chemistry Letters | 2017
Ashley Forster; Pravien Abeywickrema; Jaime Lynn Bunda; Christopher D. Cox; Tamara D. Cabalu; Melissa S. Egbertson; John F. Fay; Krista Getty; Dawn L. Hall; Maria Kornienko; Jun Lu; Gopal Parthasarathy; John C. Reid; Sujata Sharma; William D. Shipe; Sean M. Smith; Stephen Soisson; Shawn J. Stachel; Hua-Poo Su; Deping Wang; Richard Berger
We have identified a novel PDE2 inhibitor series using fragment-based screening. Pyrazolopyrimidine fragment 1, while possessing weak potency (Ki = 22.4 μM), exhibited good binding efficiencies (LBE = 0.49, LLE = 4.48) to serve as a start for structure-based drug design. With the assistance of molecular modeling and X-ray crystallography, this fragment was developed into a series of potent PDE2 inhibitors with good physicochemical properties. Compound 16, a PDE2 selective inhibitor, was identified that exhibited favorable rat pharmacokinetic properties.
ACS Medicinal Chemistry Letters | 2017
Christopher James Bungard; Peter D. Williams; Jurgen Schulz; Catherine M. Wiscount; M. Katharine Holloway; Marie Loughran; Jesse J. Manikowski; Hua-Poo Su; David Jonathan Bennett; Lehua Chang; Xin-jie Chu; Alejandro Crespo; Michael P. Dwyer; Kartik M. Keertikar; Gregori J. Morriello; Andrew Stamford; Sherman T. Waddell; Bin Zhong; Bin Hu; Tao Ji; Tracy L. Diamond; Carolyn Bahnck-Teets; Steven S. Carroll; John F. Fay; Xu Min; William J Morris; Jeanine Ballard; Michael D. Miller; John A. McCauley
Using the HIV-1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate binding bicyclic piperazine sulfonamide core was designed and synthesized. The resulting HIV-1 protease inhibitor containing this core showed an 60-fold increase in enzyme binding affinity and a 10-fold increase in antiviral activity relative to MK-8718.
Journal of Medicinal Chemistry | 2004
Anne B. Eldrup; Marija Prhavc; Jennifer L. Brooks; Balkrishen Bhat; Thazha P. Prakash; Quanlai Song; Sanjib Bera; Neelima Bhat; Prasad Dande; P. Dan Cook; C. Frank Bennett; Steven S. Carroll; Richard G. Ball; Michele Bosserman; Christine Burlein; Lawrence F. Colwell; John F. Fay; Osvaldo A. Flores; Krista Getty; Robert L. Lafemina; Joseph F. Leone; Malcolm Maccoss; Daniel R. McMasters; Joanne E. Tomassini; Derek Von Langen; and Bohdan Wolanski; David B. Olsen
Journal of Biological Chemistry | 2003
Jay A. Grobler; Eric J. Markel; John F. Fay; Donald J. Graham; Amy L. Simcoe; Steve W. Ludmerer; Edward M. Murray; Giovanni Migliaccio; Osvaldo Flores