DPC 681 and DPC 684: Potent, Selective Inhibitors of Human Immunodeficiency Virus Protease Active against Clinically Relevant Mutant Variants

Kaltenbach, Robert F.; Trainor, George L.; Getman, Daniel P.; Harris, G.; Garber, Sena; Cordova, Beverly C.; Bacheler, Lee T.; Jeffrey, Susan; Logue, Kelly; Cawood, P G; Klabe, Ronald M.; Diamond, Sharon; Davies, Meirion; Saye, Joanne; Jona, Janan; Erickson‐Viitanen, Susan

doi:10.1128/aac.45.11.3021-3028.2001

Cited by 11 publications

(7 citation statements)

References 30 publications

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“…After 3 h at room temperature, the reaction mixture was diluted with dichloromethane (30 ml) and washed successively with aqueous NaHCO 3 (2 Â 20 ml), brine (30 ml) and dried on MgSO 4 . The solvent was evaporated and a solution of the crude product in dichloromethane (10 ml) was applied to a column of silica gel.…”

Section: {3s-[(4-amino-benzenesulfonyl)-isobutylamino]-1smentioning

confidence: 99%

Isotope labeled ?HEA/HEE? moiety in the synthesis of labeled HIV-protease inhibitors?Part II

Ekhato

Liao

Plesescu

2005

J Label Compd Radiopharm

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[2H5]‐Amprenavir and [2H 5]‐saquinavir have been prepared from a common labeled precursor (1S, 2S)‐(1‐oxiranyl‐2‐[2H5]phenylethyl)‐carbamic acid tert‐butyl ester, 1. Both of these compounds are in the ‘HEA’ class of HIV protease inhibitors. [2H5]‐Indinavir, a representative of the ‘HEE’ group of protease inhibitors, has also been synthesized. In the case of indinavir, 1S‐(2,2‐dimethyl‐8, 8a‐dihydro‐3aH‐indeno‐[1,2‐d]‐oxazol‐3R‐yl)‐2‐oxiranylmethyl‐3‐[2H5]phenylpropan‐1‐one, 11, provided the [phenyl‐2H5]‐HEE core structure for synthesis of the desired labeled compound. Copyright © 2005 John Wiley & Sons, Ltd.

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Section: {3s-[(4-amino-benzenesulfonyl)-isobutylamino]-1smentioning

confidence: 99%

Isotope labeled ?HEA/HEE? moiety in the synthesis of labeled HIV-protease inhibitors?Part II

Ekhato

Liao

Plesescu

2005

J Label Compd Radiopharm

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“…The reaction mixture was concentrated to a small volume, partitioned between ethyl acetate (20 ml) and water (15 ml), and the aqueous portion was separated. The aqueous portion was further extracted with ethyl acetate (3 Â 20 ml) and the combined organic portions were washed sequentially with saturated NH 4 Cl solution (20 ml), saturated K 2 CO 3 solution (20 ml), brine (20 ml) and dried. The filtrate was evaporated to a residue (843 mg), and then dissolved in isopropyl acetate (10 ml).…”

Section: S-[n-(tert-mentioning

confidence: 99%

“…Both were selected for pre-clinical evaluation as potential new generation anti-HIV drugs. 4 Aspects of the studies involved LC-MS analysis and the stable isotopelabeled forms of DPH 153893 and DPH 140662 were needed as internal standards. We wanted to make the penta-deuterated DPH 153893 and DPH 140662 molecules in which the [ 2 H 5 ] is situated at the core as the [phenyl ring-2 H 5 ]-HEA.…”

Section: Introductionmentioning

confidence: 99%

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Isotope labeled ‘HEA Moiety’ in the synthesis of labeled HIV‐protease inhibitors – Part 1

Ekhato

Liao

Plesescu

2004

Labelled Comp Radiopharmac

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Abstract[(S)‐1′‐((N‐tert‐Butyloxycarbonyl)amino)‐2S‐[2H5]phenyl‐ethyl]oxirane 11, made from [2H5]‐bromobenzene, was transformed into the HIV‐protease inhibitors [2H5]‐DPH 153893 and [2H5]‐DPH 140662. Both compounds are members of the hydroxyethylamine class of protease inhibitors (HIV‐PIs). The method of synthesis is applicable to members of this class and the HEE group of HIV‐PIs. Copyright © 2004 John Wiley & Sons, Ltd.

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“…The technique, apart from its major use for human dosimetry estimations (Dain et al, 1994), has also been used for studies like placental transfer (Chay and Herman, 1998), brain penetration (Polli et al, 1999), and in general, assessing accumulation of drugrelated materials in organs for toxicological evaluations. DPC is a potent and selective inhibitor of HIV-1 (K i , 0.012 nM; IC 90 , 4 nM), and also of various mutant strains (IC 90 of Յ20 nM for various triple to quintuple mutant variants) (Kaltenbach et al, 2001). In the present studies, QWBA was used to determine the effect of RTV on the disposition of DPC in rats.…”

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confidence: 99%

Interaction of Ritonavir on Tissue Distribution of a [14C]L-Valinamide, a Potent Human Immunodeficiency Virus-1 Protease Inhibitor, in Rats Using Quantitative Whole-Body Autoradiography

Solon

Balani²,

Luo³

et al. 2002

Drug Metabolism and Disposition

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This article is available online at http://dmd.aspetjournals.org ABSTRACT: N-[(3-fluorophenyl)methyl]glycyl-N-{3-[((3-aminophenyl)sulfonyl)-2-(aminophenyl)amino]-(1S,2S)-2-hydroxy-1-(phenylmethyl)propyl}-3-methyl-L-valinamide (DPC 681, DPC1 ) on oral coadministration with ritonavir (RTV) in rats caused a significant increase in systemic exposure to DPC. Following a single oral dose of [ 14 C]DPC with and without RTV pretreatment in rats, and subsequent analysis of whole-body sections, prepared at 1 and 7 or 8 h postdose, using whole-body autoradiography showed an increase in radioactivity in tissues (e.g., brain, and testes) upon coadministration. The distribution of radioactivity in the brain parenchyma and ventricles was different, such that the concentration of radioactivity was greater in cerebrospinal fluid (CSF) than in central nervous system. Thus, the use of CSF concentration of the total radioactivity as a surrogate for brain penetration would result in an overestimation. DPC was determined to be metabolized prominently by rCYP3A4. The increased tissue exposure to DPC in rats could largely be attributed to inhibition of CYP3A1/2 by RTV. DPC was also a good substrate for P-glycoprotein (Pgp), with K m of 4 M and V max of 13 pmol/min. The Pgp-mediated transport of DPC across Caco-2 cells was readily saturated at >10 M and was inhibited significantly by RTV at 5 to 10 M. The data above and the reported RTV concentrations suggested that both the Pgp and CYP3A4 inhibition by RTV may play a significant role in enhancing the systemic and tissue exposure to DPC in humans.Multidrug and/or multitarget, highly active antiretroviral therapy of HIV-1 2 , to overcome progression to acquired immunodeficiency syndrome, is still a method of choice for viral suppression. There is also currently an inclusion of pharmacoenhancers in such treatments, in particular the use of RTV. RTV has been previously demonstrated to boost and maintain exposure levels for various HIV protease inhibitors, such as indinavir, amprenavir, saquinavir, lopinavir, and nalfinavir in the clinic, mainly because of inhibition of the metabolizing enzyme CYP3A4 and the transporter Pgp (Casada et al., 2000;Moyle and Back, 2001). Apart from measuring the systemic exposure to various drugs, it is imperative to determine drug distribution into various organs in which the virus can find a sanctuary (e.g., brain and testes) and escape the onslaught of drugs, allowing the virus to replicate, causing CNS damage and viral mutations. The conventional method for such measurement has been excising each organ separately, homogenizing it, followed by oxidizing and liquid scintillation counting of the trapped radioactivity. Currently, quantitative whole-body autoradiography (QWBA) has provided the means for quantitating radioactivity in whole-body sections of animals, which can determine distribution of radioactivity in many more tissue and fluid compartments (Shigematsu et al., 1995(Shigematsu et al., , 1999Zane et al., 1997;Potchoiba et al., 1998). With the contin...

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DPC 681 and DPC 684: Potent, Selective Inhibitors of Human Immunodeficiency Virus Protease Active against Clinically Relevant Mutant Variants

Abstract: Human immunodeficiency virus (HIV) protease inhibitors (PIs

Cited by 11 publications

References 30 publications

Isotope labeled ?HEA/HEE? moiety in the synthesis of labeled HIV-protease inhibitors?Part II

Isotope labeled ?HEA/HEE? moiety in the synthesis of labeled HIV-protease inhibitors?Part II

Isotope labeled ‘HEA Moiety’ in the synthesis of labeled HIV‐protease inhibitors – Part 1

Interaction of Ritonavir on Tissue Distribution of a [14C]L-Valinamide, a Potent Human Immunodeficiency Virus-1 Protease Inhibitor, in Rats Using Quantitative Whole-Body Autoradiography

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