Nancy J. Kevin
Merck & Co.
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Featured researches published by Nancy J. Kevin.
Bioorganic & Medicinal Chemistry Letters | 2001
William K. Hagmann; Philippe L. Durette; Thomas J. Lanza; Nancy J. Kevin; Stephen E. de Laszlo; Ihor E. Kopka; David N. Young; Plato A. Magriotis; Bing Li; Linus S. Lin; Ginger X. Yang; Theodore M. Kamenecka; Linda L. Chang; Jonathan E. Wilson; Malcolm Maccoss; Sander G. Mills; Gail Van Riper; Ermengilda McCauley; Linda A. Egger; Usha Kidambi; Kathryn A. Lyons; Stella H. Vincent; Ralph A. Stearns; Adria Colletti; Johannes Teffera; Sharon Tong; Judy Fenyk-Melody; Karen Owens; Dorothy Levorse; Philip Kim
Directed screening of a carboxylic acid-containing combinatorial library led to the discovery of potent inhibitors of the integrin VLA-4. Subsequent optimization by solid-phase synthesis afforded a series of sulfonylated dipeptide inhibitors with structural components that when combined in a single hybrid molecule gave a sub-nanomolar inhibitor as a lead for medicinal chemistry. Preliminary metabolic studies led to the discovery of substituted biphenyl derivatives with low picomolar activities. SAR and pharmacokinetic characterization of this series are presented.
Antimicrobial Agents and Chemotherapy | 2012
Alex G. Therien; Joann Huber; Kenneth E. Wilson; Patrick Beaulieu; Alexandre Caron; David Claveau; Kathleen Deschamps; Robert G. K. Donald; Andrew Galgoci; Michel Gallant; Xin Gu; Nancy J. Kevin; Josiane Lafleur; Penny S. Leavitt; Christian Lebeau-Jacob; Suzy Lee; Molly M. Lin; Anna A. Michels; Aimie M. Ogawa; Ronald E. Painter; Craig A. Parish; Young-Whan Park; Liliana L. Benton-Perdomo; Mihai Petcu; John W. Phillips; Mary Ann Powles; Kathryn Skorey; John Tam; Christopher M. Tan; Katherine Young
ABSTRACT The resistance of methicillin-resistant Staphylococcus aureus (MRSA) to all β-lactam classes limits treatment options for serious infections involving this organism. Our goal is to discover new agents that restore the activity of β-lactams against MRSA, an approach that has led to the discovery of two classes of natural product antibiotics, a cyclic depsipeptide (krisynomycin) and a lipoglycopeptide (actinocarbasin), which potentiate the activity of imipenem against MRSA strain COL. We report here that these imipenem synergists are inhibitors of the bacterial type I signal peptidase SpsB, a serine protease that is required for the secretion of proteins that are exported through the Sec and Tat systems. A synthetic derivative of actinocarbasin, M131, synergized with imipenem both in vitro and in vivo with potent efficacy. The in vitro activity of M131 extends to clinical isolates of MRSA but not to a methicillin-sensitive strain. Synergy is restricted to β-lactam antibiotics and is not observed with other antibiotic classes. We propose that the SpsB inhibitors synergize with β-lactams by preventing the signal peptidase-mediated secretion of proteins required for β-lactam resistance. Combinations of SpsB inhibitors and β-lactams may expand the utility of these widely prescribed antibiotics to treat MRSA infections, analogous to β-lactamase inhibitors which restored the utility of this antibiotic class for the treatment of resistant Gram-negative infections.
Bioorganic & Medicinal Chemistry Letters | 1994
Nancy J. Kevin; Ralph A. Rivero; William J. Greenlee; Raymond S.L. Chang; Tsing-Bau Chen
Abstract Incorporation of a benzoylsulfonamide and a phenylthiophene group into the potent AII antagonist L-158,809 afforded compounds with a high affinity for the AT 1 receptor. Substitution at the 5′-position of the thiophene ring dramatically increased AT 2 binding affinity provinding an analog with equal affinity for both AT 1 and AT 2 receptors.
Bioorganic & Medicinal Chemistry Letters | 1997
Craig K. Esser; Nancy J. Kevin; Nathan A. Yates; Kevin T. Chapman
Abstract A combinatorial library of N-carboxyalkyl tripeptides was prepared to generate new leads against metalloproteinases. Using the base labile TentaGel S HMB resin, an Fmoc strategy was employed to yield 100 mixtures of 200 compounds each of the general structure 5. A synthetic protocol combining both mix and split and indexed combinatorial strategies was used, and selected inhibition data against MMP-3 is reported.
Bioorganic & Medicinal Chemistry Letters | 2013
David R. Bauman; Alan Whitehead; Lisa Contino; Jisong Cui; Margarita Garcia-Calvo; Xin Gu; Nancy J. Kevin; Xiuying Ma; Lee-Yuh Pai; Kashmira Shah; Xiaolan Shen; Sloan Stribling; Hratch J. Zokian; Joe Metzger; Diane Shevell; Sherman T. Waddell
In an effort to understand the origin of blood-pressure lowering effects observed in recent clinical trials with 11β-HSD1 inhibitors, we examined a set of 11β-HSD1 inhibitors in a series of relevant in vitro and in vivo assays. Select 11β-HSD1 inhibitors reduced blood pressure in our preclinical models but most or all of the blood pressure lowering may be mediated by a 11β-HSD1 independent pathway.
Bioconjugate Chemistry | 2014
Erin N. Guidry; Julie Farand; Arash Soheili; Craig A. Parish; Nancy J. Kevin; Brenda Pipik; Kathleen Calati; Nori Ikemoto; Jacob H. Waldman; Andrew H. Latham; Bonnie J. Howell; Anthony Leone; Robert M. Garbaccio; Stephanie E. Barrett; Rubina Parmar; Quang T. Truong; Bing Mao; Ian W. Davies; Steven L. Colletti; Laura Sepp-Lorenzino
Polymer based carriers that aid in endosomal escape have proven to be efficacious siRNA delivery agents in vitro and in vivo; however, most suffer from cytotoxicity due in part to a lack of selectivity for endosomal versus cell membrane lysis. For polymer based carriers to move beyond the laboratory and into the clinic, it is critical to find carriers that are not only efficacious, but also have margins that are clinically relevant. In this paper we report three distinct categories of polymer conjugates that improve the selectivity of endosomal membrane lysis by relying on the change in pH associated with endosomal trafficking, including incorporation of low pKa heterocycles, acid cleavable amino side chains, or carboxylic acid pH sensitive charge switches. Additionally, we determine the therapeutic index of our polymer conjugates in vivo and demonstrate that the incorporation of pH responsive elements dramatically expands the therapeutic index to 10-15, beyond that of the therapeutic index (less than 3), for polymer conjugates previously reported.
Bioorganic & Medicinal Chemistry Letters | 2003
Joseph L. Duffy; Thomas A. Rano; Nancy J. Kevin; Kevin T. Chapman; William A. Schleif; David B. Olsen; Mark Stahlhut; Carrie A. Rutkowski; Lawrence C. Kuo; Lixia Jin; Jiunn H. Lin; Emilio A. Emini; James R. Tata
A biaryl pyridylfuran P(3) substituent on the hydroxyethylene isostere scaffold affords HIV protease inhibitors (PIs) with picomolar (IC(50)) potency against the protease enzymes from PI-resistant HIV-1 strains. Inclusion of a gem-dimethyl substituent afforded compound 3 with 100% oral bioavailability (dogs) and more than double the t(1/2) of indinavir. Inhibition of multiple P450 isoforms is dependent on the regiochemistry of the pyridyl nitrogen in these compounds.
Bioorganic & Medicinal Chemistry Letters | 2002
Joseph L. Duffy; Nancy J. Kevin; Brian A. Kirk; Kevin T. Chapman; William A. Schleif; David B. Olsen; Mark Stahlhut; Carrie A. Rutkowski; Lawrence C. Kuo; Lixia Jin; Jiunn H. Lin; Emilio A. Emini; James R. Tata
Substitution of the t-butylcarboxamide substituent in analogues of the HIV protease inhibitor (PI) Indinavir with a trifluoroethylamide moiety confers greater potency against both the wild-type (NL4-3) virus and PI-resistant HIV. The trifluoroethyl substituent also affords a slower clearance rate in vivo (dogs); however, this may be due to more potent inhibition of at least two P450 isoforms.
Bioorganic & Medicinal Chemistry Letters | 1996
Ralph A. Rivero; Nancy J. Kevin; Salah Kivlighn; Gloria Zingaro; Raymond S.L. Chang; William J. Greenlee
Abstract Simple modifications made to our potent angiotensin II AT 1 selective clinical candidate MK-996 provided a compound with balanced binding affinity to both the AT 1 and the AT 2 receptor subtype. This compound, L-162,389, is orally active in rats and dogs.
Bioorganic & Medicinal Chemistry Letters | 1993
Ralph A. Rivero; Nancy J. Kevin; Eric E. Allen
Abstract The biphenyl fragment of the potent angiotensin II receptor antagonist L-158,809 was replaced by a phenylthiophene and a phenylfuran moiety. Replacement of the tetrazole-bearing phenyl by a thiophene resulted in a small loss in binding affinity (