5 results on '"Parker, Dawn D."'
Search Results
2. Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir.
- Author
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Belema M, Nguyen VN, Bachand C, Deon DH, Goodrich JT, James CA, Lavoie R, Lopez OD, Martel A, Romine JL, Ruediger EH, Snyder LB, St Laurent DR, Yang F, Zhu J, Wong HS, Langley DR, Adams SP, Cantor GH, Chimalakonda A, Fura A, Johnson BM, Knipe JO, Parker DD, Santone KS, Fridell RA, Lemm JA, O'Boyle DR 2nd, Colonno RJ, Gao M, Meanwell NA, and Hamann LG
- Subjects
- Animals, Antiviral Agents chemistry, Antiviral Agents pharmacokinetics, Area Under Curve, Carbamates, Dogs, Drug Discovery, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacokinetics, Hepacivirus enzymology, Hepacivirus physiology, Imidazoles chemistry, Imidazoles pharmacokinetics, Magnetic Resonance Spectroscopy, Pyrrolidines, Rats, Spectrometry, Mass, Electrospray Ionization, Structure-Activity Relationship, Valine analogs & derivatives, Antiviral Agents pharmacology, Enzyme Inhibitors pharmacology, Hepacivirus drug effects, Imidazoles pharmacology, Viral Nonstructural Proteins antagonists & inhibitors, Virus Replication drug effects
- Abstract
The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.
- Published
- 2014
- Full Text
- View/download PDF
3. Discovery and preclinical characterization of the cyclopropylindolobenzazepine BMS-791325, a potent allosteric inhibitor of the hepatitis C virus NS5B polymerase.
- Author
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Gentles RG, Ding M, Bender JA, Bergstrom CP, Grant-Young K, Hewawasam P, Hudyma T, Martin S, Nickel A, Regueiro-Ren A, Tu Y, Yang Z, Yeung KS, Zheng X, Chao S, Sun JH, Beno BR, Camac DM, Chang CH, Gao M, Morin PE, Sheriff S, Tredup J, Wan J, Witmer MR, Xie D, Hanumegowda U, Knipe J, Mosure K, Santone KS, Parker DD, Zhuo X, Lemm J, Liu M, Pelosi L, Rigat K, Voss S, Wang Y, Wang YK, Colonno RJ, Gao M, Roberts SB, Gao Q, Ng A, Meanwell NA, and Kadow JF
- Subjects
- Allosteric Regulation, Animals, Antiviral Agents chemistry, Antiviral Agents pharmacokinetics, Benzazepines chemistry, Benzazepines pharmacokinetics, Dogs, Drug Discovery, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacokinetics, Humans, Indoles chemistry, Indoles pharmacokinetics, Magnetic Resonance Spectroscopy, Mass Spectrometry, Models, Molecular, Rats, Structure-Activity Relationship, Antiviral Agents pharmacology, Benzazepines pharmacology, Enzyme Inhibitors pharmacology, Indoles pharmacology, Viral Nonstructural Proteins antagonists & inhibitors
- Abstract
Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.
- Published
- 2014
- Full Text
- View/download PDF
4. The discovery and preclinical evaluation of BMS-707035, a potent HIV-1 integrase strand transfer inhibitor.
- Author
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Naidu, B. Narasimhulu, Walker, Michael A., Sorenson, Margaret E., Ueda, Yasutsugu, Matiskella, John D., Connolly, Timothy P., Dicker, Ira B., Lin, Zeyu, Bollini, Sagarika, Terry, Brian J., Higley, Helen, Zheng, Ming, Parker, Dawn D., Wu, Dedong, Adams, Stephen, Krystal, Mark R., and Meanwell, Nicholas A.
- Subjects
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INTEGRASES , *HIV infections , *THERAPEUTICS , *STRUCTURE-activity relationship in pharmacology , *SINGLE crystals , *X-rays , *ANTIVIRAL agents - Abstract
BMS-707035 is an HIV-1 integrase strand transfer inhibitor (INSTI) discovered by systematic optimization of N-methylpyrimidinone carboxamides guided by structure-activity relationships (SARs) and the single crystal X-ray structure of compound 10 . It was rationalized that the unexpectedly advantageous profiles of N-methylpyrimidinone carboxamides with a saturated C2-substitutent may be due, in part, to the geometric relationship between the C2-substituent and the pyrimidinone core. The single crystal X-ray structure of 10 provided support for this reasoning and guided the design of a spirocyclic series 12 which led to discovery of the morpholino-fused pyrimidinone series 13 . Several carboxamides derived from this bicyclic scaffold displayed improved antiviral activity and pharmacokinetic profiles when compared with corresponding spirocyclic analogs. Based on the excellent antiviral activity, preclinical profiles and acceptable in vitro and in vivo toxicity profiles, 13a (BMS-707035) was selected for advancement into phase I clinical trials. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
5. C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors.
- Author
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Liu, Zheng, Swidorski, Jacob J., Nowicka-Sans, Beata, Terry, Brian, Protack, Tricia, Lin, Zeyu, Samanta, Himadri, Zhang, Sharon, Li, Zhufang, Parker, Dawn D., Rahematpura, Sandhya, Jenkins, Susan, Beno, Brett R., Krystal, Mark, Meanwell, Nicholas A., Dicker, Ira B., and Regueiro-Ren, Alicia
- Subjects
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BENZOIC acid , *CHEMICAL derivatives , *HIV infections , *THERAPEUTICS , *DRUG design , *HETEROCYCLIC compound derivatives , *ANTIVIRAL agents , *CHEMICAL synthesis , *CELL-mediated cytotoxicity , *CELL culture , *HESPEROYUCCA - Abstract
A series of C-3 phenyl- and heterocycle-substituted derivatives of C-3 deoxybetulinic acid and C-3 deoxybetulin was designed and synthesized as HIV-1 maturation inhibitors (MIs) and evaluated for their antiviral activity and cytotoxicity in cell culture. A 4-subsituted benzoic acid moiety was identified as an advantageous replacement for the 3′3′-dimethylsuccinate moiety present in previously disclosed MIs that illuminates new aspects of the topography of the pharmacophore. The new analogs exhibit excellent in vitro antiviral activity against wild-type (wt) virus and a lower serum shift when compared with the prototypical HIV-1 MI bevirimat ( 1 , BVM), the first MI to be evaluated in clinical studies. Compound 9a exhibits comparable cell culture potency toward wt virus as 1 (WT EC 50 = 16 nM for 9a compared to 10 nM for 1 ). However, the potency of 9a is less affected by the presence of human serum, while the compound displays a similar pharmacokinetic profile in rats to 1 . Hence 9a , the 4-benzoic acid derivative of deoxybetulinic acid, represents a new starting point from which to explore the design of a 2nd generation MI. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
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