Structure–activity relationships of diamine inhibitors of cytochrome P450 (CYP) 3A as novel pharmacoenhancers. Part II: P2/P3 region and discovery of cobicistat (GS-9350)

Xu, Lianhong; Liu, Hongtao; Hong, Allen Y.; Vivian, Randall W.; Murray, Bernard P.; Callebaut, Christian; Choi, Y.; Lee, Melody S.; Chau, Jennifer; Tsai, Luke Y.; Stray, Kirsten M.; Strickley, Robert G.; Wang, Jianhong; Tong, L.; Swaminathan, S.; Rhodes, Gerry; Desai, Manoj C.

doi:10.1016/j.bmcl.2013.12.057

Cited by 24 publications

(16 citation statements)

References 16 publications

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“…The first two INSTIs, raltegravir (RAL) and elvitegravir (EVG), have been approved for clinical use as components of combination antiretroviral therapy. Although both INSTIs have displayed good antiviral efficacy as components of combination regimens in the treatment of HIV-1 infections in randomized trials (3), RAL is dosed twice daily (4–6) while EVG is dosed once daily but requires coadministration with a pharmacokinetic enhancer to increase EVG systemic exposure (7–9). In addition, RAL and EVG have an overlapping resistance profile such that many viruses resistant to one drug are cross-resistant to the other drug, which ultimately precludes the sequential use of these two INSTIs (10–15).…”

Section: Introductionmentioning

confidence: 99%

Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer Inhibitor with an Improved Resistance Profile

Tsiang

Jones

Goldsmith

et al. 2016

Antimicrob Agents Chemother

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Bictegravir (BIC; GS-9883), a novel, potent, once-daily, unboosted inhibitor of HIV-1 integrase (IN), specifically targets IN strand transfer activity (50% inhibitory concentration [IC50] of 7.5 ± 0.3 nM) and HIV-1 integration in cells. BIC exhibits potent and selective in vitro antiretroviral activity in both T-cell lines and primary human T lymphocytes, with 50% effective concentrations ranging from 1.5 to 2.4 nM and selectivity indices up to 8,700 relative to cytotoxicity. BIC exhibits synergistic in vitro antiviral effects in pairwise combinations with tenofovir alafenamide, emtricitabine, or darunavir and maintains potent antiviral activity against HIV-1 variants resistant to other classes of antiretrovirals. BIC displayed an in vitro resistance profile that was markedly improved compared to the integrase strand transfer inhibitors (INSTIs) raltegravir (RAL) and elvitegravir (EVG), and comparable to that of dolutegravir (DTG), against nine INSTI-resistant site-directed HIV-1 mutants. BIC displayed statistically improved antiviral activity relative to EVG, RAL, and DTG against a panel of 47 patient-derived HIV-1 isolates with high-level INSTI resistance; 13 of 47 tested isolates exhibited >2-fold lower resistance to BIC than DTG. In dose-escalation experiments conducted in vitro, BIC and DTG exhibited higher barriers to resistance than EVG, selecting for HIV-1 variants with reduced phenotypic susceptibility at days 71, 87, and 20, respectively. A recombinant virus with the BIC-selected M50I/R263K dual mutations in IN exhibited only 2.8-fold reduced susceptibility to BIC compared to wild-type virus. All BIC-selected variants exhibited low to intermediate levels of cross-resistance to RAL, DTG, and EVG (<8-fold) but remained susceptible to other classes of antiretrovirals. A high barrier to in vitro resistance emergence for both BIC and DTG was also observed in viral breakthrough studies in the presence of constant clinically relevant drug concentrations. The overall virologic profile of BIC supports its ongoing clinical investigation in combination with other antiretroviral agents for both treatment-naive and -experienced HIV-infected patients.

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Section: Introductionmentioning

confidence: 99%

Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer Inhibitor with an Improved Resistance Profile

Tsiang

Jones

Goldsmith

et al. 2016

Antimicrob Agents Chemother

Self Cite

235

183

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“…Like ritonavir, cobicistat does inhibit CYP2D6, but only weakly. It also inhibits the organic anion transport proteins (OATP)1B1 and 1B3 and MATE-1 [21][22][23]36,37]. Cobicistat is however not an inducer of CYP 1A2, 2B6, 2C8, 2C9, 2C19 or UGT1A1 or efflux transporter proteins [21][22][23].…”

Section: Differing Effects Of Cobicistat and Ritonavir On Metabolic Enzmentioning

confidence: 99%

“…This profile gives a reduced potential for selection of PI-resistant mutants by cobicistat compared with ritonavir [21,22]. Cobicistat also has less pronounced effects on adipocytes than ritonavir [21], and as such may have less potential for disturbance of lipid metabolism.…”

mentioning

confidence: 93%

“…Cobicistat (formerly GS-9350) is a new pharmacokinetic enhancer with no antiviral activity that also inhibits CYP3A, although more selectively than ritonavir in vitro [21][22][23]. In Phase I studies, cobicistat was shown to be a comparable pharmacokinetic enhancer to ritonavir when combined with atazanavir, the integrase inhibitor elvitegravir, or midazolam (a CYP3A probe substrate) [23][24][25].…”

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confidence: 99%

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Darunavir/cobicistat once daily for the treatment of HIV

Kakuda

Crauwels

Opsomer

et al. 2015

Expert Review of Anti-infective Therapy

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A current focus in HIV management is improving adherence by minimizing pill burden with convenient formulations, including fixed-dose combinations (FDCs). Darunavir, a HIV protease inhibitor, co-administered with low-dose ritonavir (800/100 mg once daily), is recommended in guidelines in combination with other antiretrovirals for HIV patients with no darunavir resistance-associated mutations. Cobicistat is an alternative agent to ritonavir for boosting plasma drug levels of darunavir among other antiretrovirals. Cobicistat is a more specific cytochrome P450 3A inhibitor than ritonavir without enzyme-inducing properties. This review describes the differing effects of cobicistat and ritonavir on metabolic enzymes, which explains their differing drug-drug interactions, and summarizes some of the studied drug-drug interactions for cobicistat. It also outlines the clinical development and data for a once-daily darunavir/cobicistat FDC. This FDC thus allows for a once-daily treatment regimen (including background antiretrovirals) with reduced pill burden.

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“…Raltegravir (RAL) was the first IN strand-transfer inhibitor (INSTI) to be approved for clinical use and is dosed twice daily [3][4][5]. Elvitegravir (EVG) is co-administered with cobicistat, a new pharmacokinetic enhancer that enables once-daily dosing of EVG [6][7][8]. A once-daily single tablet regimen (STRIBILD TM ) containing EVG, cobicistat, deoxyfluorothiacytidine (FTC) and tenofovir disoproxil fumarate (TDF) has been recently approved by the FDA for the treatment of HIV infection.…”

Section: Introductionmentioning

confidence: 99%

Preclinical and Clinical Profile of HIV-1 Integrase Strand-transfer Inhibitor GS-9224 Compared to its Parent Compound GS-9160

Hluhanich¹

2014

J Antivir Antiretrovir

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Materials and Methods Compounds GS-9224 and GS-9160 were synthesized at Gilead Sciences, Inc. L-870,810 was synthesized by Combi Blocks, Inc. (San Diego, CA). RAL was synthesized by Naeja Pharmaceuticals, Inc. (Edmonton, Alberta Canada). All three compounds have a purity of >95% as determined by analytical reversed phase HPLC using a Phenomenex Luna C18 column and UV detection at 214 nm and 254 nm. The structures of these three INSTIs are shown in (Figure 1). Cells MT-2 cells were obtained from Stanford University and MT-4 cells were obtained from the NIH AIDS Research and Reference Reagent Program (Germantown, MD). SupT1 cells were obtained from the American Type Culture Collection (Rockville, MD). MT-2, MT-4 and SupT1 cells were maintained in RPMI-1640 medium (Cat # 61870

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Structure–activity relationships of diamine inhibitors of cytochrome P450 (CYP) 3A as novel pharmacoenhancers. Part II: P2/P3 region and discovery of cobicistat (GS-9350)

Cited by 24 publications

References 16 publications

Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer Inhibitor with an Improved Resistance Profile

Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer Inhibitor with an Improved Resistance Profile

Darunavir/cobicistat once daily for the treatment of HIV

Preclinical and Clinical Profile of HIV-1 Integrase Strand-transfer Inhibitor GS-9224 Compared to its Parent Compound GS-9160

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