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ABSTRACT: The HCV non-structural protein NS5A has been established as a viable target for the development of direct acting antiviral therapy. From computational modeling studies strong intra-molecular hydrogen bonds were found to be a common structural moiety within known NS5A inhibitors that have low pico-molar replicon potency. Efforts to reproduce these γ-turn-like substructures provided a novel NS5A inhibitor based on a fluoro-olefin isostere. This fluoro-olefin containing inhibitor exhibited picomolar activity (EC(50)=79 pM) against HCV genotype 1b replicon without measurable cytotoxicity. This level of activity is comparable to the natural peptide-based inhibitors currently under clinic evaluation, and demonstrates that a peptidomimetic approach can serve as a useful strategy to produce potent and structurally unique inhibitors of HCV NS5A.
Bioorganic & medicinal chemistry letters 02/2012; 22(8):2938-42. · 2.65 Impact Factor
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Weiguo Liu,
Fiona Lau,
Kun Liu,
Harold B Wood,
Gaochao Zhou,
Yuli Chen,
Ying Li,
Taro E Akiyama,
Gino Castriota,
Monica Einstein,
Chualin Wang,
Margaret E McCann,
Thomas W Doebber,
Margaret Wu,
Ching H Chang,
Lesley McNamara,
Brian McKeever, Ralph T Mosley,
Joel P Berger,
Peter T Meinke
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ABSTRACT: A series of benzimidazolone carboxylic acids and oxazolidinediones were designed and synthesized in search of selective PPARγ modulators (SPPARγMs) as potential therapeutic agents for the treatment of type II diabetes mellitus (T2DM) with improved safety profiles relative to rosiglitazone and pioglitazone, the currently marketed PPARγ full agonist drugs. Structure-activity relationships of these potent and highly selective SPPARγMs were studied with a focus on their unique profiles as partial agonists or modulators. A variety of methods, such as X-ray crystallographic analysis, PPARγ transactivation coactivator profiling, gene expression profiling, and mutagenesis studies, were employed to reveal the differential interactions of these new analogues with PPARγ receptor in comparison to full agonists. In rodent models of T2DM, benzimidazolone analogues such as (5R)-5-(3-{[3-(5-methoxybenzisoxazol-3-yl)benzimidazol-1-yl]methyl}phenyl)-5-methyloxazolidinedione (51) demonstrated efficacy equivalent to that of rosiglitazone. Side effects, such as fluid retention and heart weight gain associated with PPARγ full agonists, were diminished with 51 in comparison to rosiglitazone based on studies in two independent animal models.
Journal of Medicinal Chemistry 11/2011; 54(24):8541-54. · 4.80 Impact Factor
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Monica Einstein,
Taro E Akiyama,
Gino A Castriota,
Chuanlin F Wang,
Brian McKeever, Ralph T Mosley,
Joseph W Becker,
David E Moller,
Peter T Meinke,
Harold B Wood,
Joel P Berger
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ABSTRACT: Despite their proven antidiabetic efficacy, widespread use of peroxisome proliferator-activated receptor (PPAR)gamma agonists has been limited by adverse cardiovascular effects. To overcome this shortcoming, selective PPARgamma modulators (SPPARgammaMs) have been identified that have antidiabetic efficacy comparable with full agonists with improved tolerability in preclinical species. The results of structural studies support the proposition that SPPARgammaMs interact with PPARgamma differently from full agonists, thereby providing a physical basis for their novel activities. Herein, we describe a novel PPARgamma ligand, SPPARgammaM2. This compound was a partial agonist in a cell-based transcriptional activity assay, with diminished adipogenic activity and an attenuated gene signature in cultured human adipocytes. X-ray cocrystallography studies demonstrated that, unlike rosiglitazone, SPPARgammaM2 did not interact with the Tyr473 residue located within helix 12 of the ligand binding domain (LBD). Instead, SPPARgammaM2 was found to bind to and activate human PPARgamma in which the Tyr473 residue had been mutated to alanine (hPPARgammaY473A), with potencies similar to those observed with the wild-type receptor (hPPARgammaWT). In additional studies, we found that the intrinsic binding and functional potencies of structurally distinct SPPARgammaMs were not diminished by the Y473A mutation, whereas those of various thiazolidinedione (TZD) and non-TZD PPARgamma full agonists were reduced in a correlative manner. These results directly demonstrate the important role of Tyr473 in mediating the interaction of full agonists but not SPPARgammaMs with the PPARgamma LBD, thereby providing a precise molecular determinant for their differing pharmacologies.
Molecular pharmacology 02/2008; 73(1):62-74. · 4.53 Impact Factor
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Timothy A Blizzard,
Candido Gude,
Jerry D Morgan,
Wanda Chan,
Elizabeth T Birzin,
Marina Mojena,
Consuelo Tudela,
Fang Chen,
Kristin Knecht,
Qin Su,
Bryan Kraker, Ralph T Mosley,
Mark A Holmes,
Susan P Rohrer,
Milton L Hammond
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ABSTRACT: A series of androstene-3,5-diene derivatives were prepared. Despite lacking the C-3 hydroxyl previously believed necessary for ER activity, some of the analogs retained surprising affinity for ER-beta. For example, diene 4 retained excellent selectivity and potency as an ER-beta agonist and was more selective for ER-beta over the androgen receptor (AR).
Bioorganic & Medicinal Chemistry Letters 12/2007; 17(22):6295-8. · 2.55 Impact Factor
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Christopher F Thompson,
Nazia Quraishi,
Amjad Ali, Ralph T Mosley,
James R Tata,
Milton L Hammond,
James M Balkovec,
Monica Einstein,
Lan Ge,
Georgianna Harris, [......],
Chuanlin Wang,
Joanne Williamson,
Douglas K Miller,
Ting-Ting D Yamin,
Chris M Thompson,
Edward A O'Neill,
Dennis Zaller,
Michael J Forrest,
Ester Carballo-Jane,
Silvi Luell
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ABSTRACT: Chemistry was developed to synthesize the title series of compounds. The ability of these novel ligands to bind to the glucocorticoid receptor was investigated. These compounds were also tested in a series of functional assays and some were found to display the profile of a dissociated glucocorticoid. The SAR of the 6,5-bicyclic series differed markedly from the previously reported 6,6-series. Molecular modeling studies were employed to understand the conformational differences between the two series of compounds, which may explain their divergent activity. Two compounds were profiled in vivo and shown to reduce inflammation in a mouse model. An active metabolite is suspected in one case.
Bioorganic & Medicinal Chemistry Letters 07/2007; 17(12):3354-61. · 2.55 Impact Factor
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Kevin D Dykstra,
Liangqin Guo,
Elizabeth T Birzin,
Wanda Chan,
Yi Tien Yang,
Edward C Hayes,
Carolyn A DaSilva,
Lee-Yuh Pai, Ralph T Mosley,
Bryan Kraker,
Paula M D Fitzgerald,
Frank DiNinno,
Susan P Rohrer,
James M Schaeffer,
Milton L Hammond
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ABSTRACT: A novel class of indole ligands for estrogen receptor alpha have been discovered which exhibit potent affinity and high selectivity. Substitution of the bazedoxifene skeleton to the linker present in the HTS lead 1a provided 22b which was found to be 130-fold alpha-selective and acted as an antagonist of estradiol activity in uterine tissue and MCF-7 cancer cells.
Bioorganic & Medicinal Chemistry Letters 05/2007; 17(8):2322-8. · 2.55 Impact Factor
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ABSTRACT: A series of 2-9a bridged tetrahydrofluorenone derivatives were prepared which exhibited significant binding affinity for ERbeta and were highly selective.
Bioorganic & Medicinal Chemistry Letters 10/2006; 16(17):4462-6. · 2.55 Impact Factor
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Timothy A Blizzard,
Candido Gude,
Jerry D Morgan,
Wanda Chan,
Elizabeth T Birzin,
Marina Mojena,
Consuelo Tudela,
Fang Chen,
Kristin Knecht,
Qin Su,
Bryan Kraker, Ralph T Mosley,
Mark A Holmes,
Nandini Sharma,
Paula M D Fitzgerald,
Susan P Rohrer,
Milton L Hammond
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ABSTRACT: A series of 19-substituted androstenediol derivatives was prepared. Some of the novel analogs were surprisingly potent and selective ligands for ER-beta.
Bioorganic & Medicinal Chemistry Letters 03/2006; 16(4):834-8. · 2.55 Impact Factor
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Timothy A Blizzard,
Jerry D Morgan,
Wanda Chan,
Elizabeth T Birzin,
Lee-Yuh Pai,
Edward C Hayes,
Carolyn A DaSilva, Ralph T Mosley,
Yi Tien Yang,
Susan P Rohrer,
Frank Dininno,
Milton L Hammond
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ABSTRACT: Two novel side chains which had previously been found to enhance antagonist activity in the dihydrobenzoxathiin SERM series were applied to three existing platforms. The novel side chains did not improve the antagonist activity of the existing platforms.
Bioorganic & Medicinal Chemistry Letters 01/2006; 15(23):5124-8. · 2.55 Impact Factor
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Zhixiong Ye,
Tanya MacNeil,
David H Weinberg,
Rubana N Kalyani,
Rui Tang,
Alison M Strack,
Beth A Murphy, Ralph T Mosley,
D Euan MacIntyre,
Lex H T Van der Ploeg,
Arthur A Patchett,
Matthew J Wyvratt,
Ravi P Nargund
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ABSTRACT: The melanocortin subtype-4 receptor (MC4R) has been implicated in the control of feeding behavior and body weight regulation. A series of tetrapeptides, based on Tic-DPhe-Arg-Trp-NH2-a mimic of the putative message sequence "His-Phe-Arg-Trp" and modified at the DPhe position, were prepared and pharmacologically characterized for potency and selectivity. Substitution of His with Tic gave peptides with significant increases in selectivity. The effects of the substitution pattern of DPhe were investigated and it has significant influences on potency and the level of the maximum cAMP accumulation. Intracerebroventricular administration of peptide 10 induced significant inhibition of cumulative overnight food intake and feeding duration in rats.
Peptides 11/2005; 26(10):2017-25. · 2.43 Impact Factor
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ABSTRACT: Reagent Selector is an intranet-based tool that aids in the selection of reagents for use in combinatorial library construction. The user selects an appropriate reagent group as a query, for example, primary amines, and further refines it on the basis of various physicochemical properties, resulting in a list of potential reagents. The results of this selection process are, in turn, converted into synthons: the fragments or R-groups that are to be incorporated into the combinatorial library. The Synthon Analysis interface graphically depicts the chemical properties for each synthon as a function of the topological bond distance from the scaffold attachment point. Displayed in this fashion, the user is able to visualize the property space for the universe of synthons as well as that of the synthons selected. Ultimately, the reagent list that embodies the selected synthons is made available to the user for reagent procurement. Application of the approach to a sample reagent list for a G-protein coupled receptor targeted library is described.
Journal of Chemical Information and Modeling 07/2005; 45(5):1439-46. · 4.68 Impact Factor
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Jian Liu,
Elizabeth T Birzin,
Wanda Chan,
Yi Tien Yang,
Lee-Yuh Pai,
Carolyn Dasilva,
Edward C Hayes, Ralph T Mosley,
Frank Dininno,
Susan P Rohrer,
James M Schaeffer,
Milton L Hammond
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ABSTRACT: The ring oxygen and sulfur analogs of lasofoxifene, 1a and 1b, were synthesized in an attempt to impart ERalpha selectivity, as found in the closely related dihydrobenzoxathiin compound I, recently discovered in these laboratories. The resulting isochroman and isothiochroman compounds were found to exhibit equipotent binding affinities to the ER isoforms and were less active in the inhibition of estradiol-triggered uterine growth when compared to I and lasofoxifene.
Bioorganic & Medicinal Chemistry Letters 03/2005; 15(3):715-8. · 2.55 Impact Factor
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Monica Einstein,
Mark Greenlee,
Greg Rouen,
Ayesha Sitlani,
Joe Santoro,
Chuanlin Wang,
Shilpa Pandit,
Paul Mazur,
Isabella Smalera,
Alehna Pm Weaver,
Ying Ying Zeng,
Lan Ge,
Theresa Kelly,
Tony Paiva,
Wayne Geissler, Ralph T Mosley,
Joanne Williamson,
Amjad Ali,
Jim Balkovec,
Georgianna Harris
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ABSTRACT: Glucocorticoids (GCs) are vital multi-faceted hormones with recognized effects on carbohydrate, protein and lipid metabolism. Previous studies with the steroid antagonist, RU486 have underscored the essential role of GCs in the regulation of these metabolic pathways. This article describes the discovery and characterization of novel GRalpha selective nonsteroidal antagonists (NSGCAs). NSGCAs 2 and 3 are spirocyclic dihydropyridine derivatives that selectively bind the GRalpha with IC(50s) of 2 and 1.5 nM, respectively. Importantly, these compounds are full antagonists of the induction by dexamethasone (Dex) of marker genes for glucose and glutamine metabolism; the tyrosine amino transferase (TAT) and glutamine synthetase (GS) enzymes, respectively. In contrast, GC-dependent transcriptional repression of the collagenase 1 (MMP-1) enzyme, an established GRalpha responsive proinflammatory gene; is poorly antagonized by these compounds. These NSGCAs might have useful applications as tools in metabolic research and drug discovery.
The Journal of Steroid Biochemistry and Molecular Biology 01/2005; 92(5):345-56. · 3.05 Impact Factor
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Seongkon Kim,
Jane Y Wu,
Elizabeth T Birzin,
Katalin Frisch,
Wanda Chan,
Lee-Yuh Pai,
Yi Tien Yang, Ralph T Mosley,
Paula M D Fitzgerald,
Nandini Sharma,
Johanna Dahllund,
Ann-Gerd Thorsell,
Frank DiNinno,
Susan P Rohrer,
James M Schaeffer,
Milton L Hammond
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ABSTRACT: The discovery and synthesis of dihydrobenzoxathiins as potent, ERalpha subtype selective ligands are described. The most active analogue, 4-D, was found to be 50-fold selective in a competitive binding assay and 100-fold selective in a transactivation assay in HEK-293 cells. The alpha selectivity was postulated to lie in the interaction of the sulfur atom of the benzoxathiin ring with the two discriminating residues in the binding pocket of the receptor isoforms.
Journal of Medicinal Chemistry 05/2004; 47(9):2171-5. · 5.25 Impact Factor
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ABSTRACT: A series of 2-phenylspiroindenediones was prepared. The spiroindenediones were found to be less active than the corresponding spiroindenes as estrogen receptor ligands and failed to demonstrate the receptor subtype selectivity that had been anticipated from molecular modeling.
Bioorganic & Medicinal Chemistry Letters 04/2004; 14(5):1317-21. · 2.55 Impact Factor
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Helen Y Chen,
Kevin D Dykstra,
Elizabeth T Birzin,
Katalin Frisch,
Wanda Chan,
Yi T Yang, Ralph T Mosley,
Frank DiNinno,
Susan P Rohrer,
James M Schaeffer,
Milton L Hammond
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ABSTRACT: A class of flavanoids exhibiting a high degree of selectivity for ERalpha over ERbeta has been discovered. The most active analogue 6 was found to be 66-fold ERalpha-selective and demonstrated uterine estradiol antagonism.
Bioorganic & Medicinal Chemistry Letters 04/2004; 14(6):1417-21. · 2.55 Impact Factor
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ABSTRACT: Melanocortin receptor 4 (MC-4R) is involved in the regulation of energy balance and body weight, and recognizes alpha-, beta-, and gamma-melanocyte stimulating hormones (alpha-, beta-, gamma-MSH). In the search for compounds that regulate food intake and body weight, two synthetic lactam-derivative ligands of alpha-MSH were discovered, MTII and SHU9119. MTII is an agonist and reduces food intake in rats, whereas SHU9119 is an antagonist, and increases food intake and body weight in rats. MTII and SHU9119 are nonselective compounds to MC-4R. To enhance the potency and selectivity at the human MC-4R (hMC-4R), we recently synthesized analogs of SHU9119 (M. A. Bednarek, T. MacNeil, R. N. Kalyani, R. Tang, Van der L. H. T. Ploeg, and D. H. Weinberg, Journal of Medicinal Chemistry, 2001, Vol. 44, pp. 401-409), wherein compound 1 was the most selective for hMC-4R. Replacement of D-Nal by L-Nal in compound 1 made compound 2 weakly active. Comparison of the structures by NMR and molecular modeling of compounds 1 and 2 vs SHU9119 and MTII indicated that, even though they existed as an average of several conformations in solution, there were distinctions in their structures. The gamma-methylene protons of Arg in compound 1 were nonequivalent and shielded probably by the aromatic ring of Nal. The NHi-NHi+1 NOE cross peaks and the temperature coefficients of the amide protons around the "essential core" Nal/Phe7-Arg8-Trp9, required for high affinity and high selectivity at hMC-4R, were indicative of a possible turn structure for these compounds but with differences in their NOE strengths and temperature coefficient values. Molecular modeling of these compounds based on their NMR data showed that the essential core appeared as a "V" shape with two different orientations, one for compound 1 and some of the conformers of SHU9119 and MTII, and the other for compound 2 and some other conformers of SHU9119 and MTII. The remaining conformers of SHU9119 and MTII, which did not map to compound 1 or 2, suggested that they were outside of the hMC-4R binding envelop. These observations may lead to conjectures as to why compound 1 is highly active and selective toward hMC-4R.
Biopolymers 05/2003; 68(4):512-27. · 2.87 Impact Factor
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ABSTRACT: A series of 2-phenylspiroindenes was prepared. The most active analogue (2) was found to be comparable in potency to raloxifene (1) as an estrogen receptor ligand.
Bioorganic & Medicinal Chemistry Letters 03/2003; 13(3):479-83. · 2.55 Impact Factor
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ABSTRACT: Pastor and Cruciani [J. Med. Chem. 38 (1995) 4637] and Kastenholz et al. [J. Med. Chem. 43 (2000) 3033] pioneered methods for comparing related receptors, with the ultimate goal of designing selective ligands. Such methods start with a reasonable superposition of high-resolution three-dimensional (3D) structures of the receptors. Next, molecular field maps are calculated for each receptor. Then the maps are analyzed to determine which map features are correlated with a particular subset of receptors. We present a method FLOGTV, based on the trend vector paradigm [J. Chem. Inf. Comput. Sci. 25 (1985) 64] to perform the analysis. This is mathematically simpler than the GRID/CPCA method of Kastenholz et al. and allows for the simultaneous comparison of many receptor structures. Also, the trend vector paradigm provides a method of selecting isopotential contours that are well above "noise". We demonstrate the method on four examples: HIV proteases versus two-domain acid proteases, thrombin versus trypsin and factor Xa, bacterial dihydrofolate reductases (DHFRs) versus vertebrate DHFRs, and P38 versus ERK protein kinases.
Journal of Molecular Graphics and Modelling 01/2003; 21(3):217-25. · 2.18 Impact Factor
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Subharekha Raghavan,
Zheng Yang, Ralph T Mosley,
William A Schleif,
Lori Gabryelski,
David B Olsen,
Mark Stahlhut,
Lawrence C Kuo,
Emilio A Emini,
Kevin T Chapman,
James R Tata
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ABSTRACT: A 1X22X41 combinatorial library or 902 compounds of indinavir analogues was synthesized on the solid support to identify a replacement for the aminoindanol moiety at P2'. 2,6-Dimethyl-4-hydroxy phenol was discovered to be a good replacement for aminoindanol.
Bioorganic & Medicinal Chemistry Letters 11/2002; 12(20):2855-8. · 2.55 Impact Factor
