Helen J. Mitchell
Merck & Co.
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Publication
Featured researches published by Helen J. Mitchell.
Journal of Biological Chemistry | 2010
Azriel Schmidt; Donald B. Kimmel; Chang Bai; Angela Scafonas; SuJane Rutledge; Robert L. Vogel; Sheila McElwee-Witmer; Fang Chen; Pascale V. Nantermet; Viera Kasparcova; Chih-Tai Leu; Hai-Zhuan Zhang; Mark E. Duggan; Michael A. Gentile; Paul Hodor; Brenda Pennypacker; Patricia Masarachia; Evan E. Opas; Sharon Adamski; Tara E. Cusick; Jiabing Wang; Helen J. Mitchell; Yuntae Kim; Thomayant Prueksaritanont; James J. Perkins; Robert S. Meissner; George D. Hartman; Leonard P. Freedman; Shun-ichi Harada; William J. Ray
Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize the AR, but how these complex activities translate into tissue selectivity is not known. Here, we probed receptor function using >1000 synthetic AR ligands. These compounds produced a spectrum of activities in each assay ranging from 0 to 100% of maximal response. By testing different classes of compounds in ovariectomized rats, we established that ligands that transactivated a model promoter 40–80% of an agonist, recruited the coactivator GRIP-1 <15%, and stabilized the N-/C-terminal interdomain interaction <7% induced bone formation with reduced effects in the uterus and in sebaceous glands. Using these criteria, multiple SARMs were synthesized including MK-0773, a 4-aza-steroid that exhibited tissue selectivity in humans. Thus, AR activated to moderate levels due to reduced cofactor recruitment, and N-/C-terminal interactions produce a fully anabolic response, whereas more complete receptor activation is required for reproductive effects. This bimodal activation provides a molecular basis for the development of SARMs.
Journal of Medicinal Chemistry | 2009
Helen J. Mitchell; William P. Dankulich; George D. Hartman; Thomayant Prueksaritanont; Azriel Schmidt; Robert L. Vogel; Chang Bai; Sheila McElwee-Witmer; Hai Z. Zhang; Fang Chen; Chih-Tai Leu; Donald B. Kimmel; William J. Ray; Pascale V. Nantermet; Michael A. Gentile; Mark E. Duggan; Robert S. Meissner
A novel series of 16-substituted-4-azasteroids has been identified as potential tissue-selective androgen receptor modulators. These ligands display potent hAR binding and agonist activity, low virilizing potential, and good pharmacokinetic profiles in dogs. On the basis of its in vitro profile, 21 was evaluated in the OVX and ORX rat models and exhibited an osteoanabolic, tissue-selective profile.
European Journal of Pharmacology | 2014
Philip E. Brandish; Kenneth Anderson; Gretchen A. Baltus; Chang Bai; Christopher James Bungard; Patricia B. Bunting; Alan Byford; Chi-Sung Chiu; Milenko Cicmil; Halea A. Corcoran; Danielle Euler; John E. Fisher; Carlo Gambone; Martha Hasbun-Manning; Nelly A. Kuklin; Elizabeth Landis; Traci Q. Lifsted; Sheila McElwee-Witmer; Ian McIntosh; Robert S. Meissner; John Miao; Helen J. Mitchell; Amy Musselman; Azriel Schmidt; John H. Shin; Peter Szczerba; Charles D. Thompson; Catherine Tribouley; Robert L. Vogel; Sudha Warrier
Glucocorticoids are used widely in the treatment of inflammatory diseases, but use is accompanied by a significant burden of adverse effects. It has been hypothesized that gene- and cell-specific regulation of the glucocorticoid receptor by small molecule ligands could be translated into a therapeutic with an improved risk-benefit profile. MK-5932 is a highly selective glucocorticoid receptor modulator that is anti-inflammatory in vivo with an improved profile on glucose metabolism: Bungard et al. (2011). Bioorg. Med. Chem. 19, 7374-7386. Here we describe the full biological profile of MK-5932. Cytokine production following lipopolysaccharide (LPS) challenge was blocked by MK-5932 in both rat and human whole blood. Oral administration reduced inflammatory cytokine levels in the serum of rats challenged with LPS. MK-5932 was anti-inflammatory in a rat contact dermatitis model, but was differentiated from 6-methylprednisolone by a lack of elevation of fasting insulin or glucose levels after 7 days of dosing, even at high exposure levels. In fact, animals in the vehicle group were consistently hyperglycemic at the end of the study, and MK-5932 normalized glucose levels in a dose-dependent manner. MK-5932 was also anti-inflammatory in the rat collagen-induced arthritis and adjuvant-induced arthritis models. In healthy dogs, oral administration of MK-5932 exerted acute pharmacodynamic effects with potency comparable to prednisone, but with important differences on neutrophil counts, again suggestive of a dissociated profile. Important gaps in our understanding of mechanism of action remain, but MK-5932 will be a useful tool in dissecting the mechanisms of glucose dysregulation by therapeutic glucocortiocids.
Journal of Organic Chemistry | 1994
Helen J. Mitchell; Yves Leblanc
Archive | 2004
Mildred L. Kaufman; Robert S. Meissner; Helen J. Mitchell
Archive | 2004
William P. Dankulich; Mildred L. Kaufman; Robert S. Meissner; Helen J. Mitchell
Archive | 2005
Barbara Hanney; Yuntae Kim; Michael R Krout; Robert S. Meissner; Helen J. Mitchell; Jeffrey Musselman; James J. Perkins; Jiabing Wang
Archive | 2009
William P. Dankulich; Mildred L. Kaufman; Danielle M. Mcmaster; Robert S. Meissner; Helen J. Mitchell
Archive | 2011
Ian M. Bell; Mark E. Fraley; Steven N. Gallicchio; Anthony Ginnetti; Helen J. Mitchell; Daniel V. Paone; Donnette D. Staas; Heather E. Stevenson; Cheng Wang; C. Blair Zartman
Archive | 2011
Ian M. Bell; Mark E. Fraley; Steven N. Gallicchio; Anthony Ginnetti; Helen J. Mitchell; Daniel V. Paone; Donnette D. Staas; Cheng Wang; Blair C. Zartman; Heather E. Stevenson