Carbamoyl Pyridone HIV-1 Integrase Inhibitors 3. A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and the Discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744)

Johns, Brian A.; Kawasuji, Takashi; Taishi, Teruhiko; Temelkoff, David P.; Yoshida, Hiroshi; Akiyama, Tsuyoshi; Taoda, Yoshiyuki; Murai, Hitoshi; Kiyama, Ryuichi; Fuji, Masahiro; Tánimoto, Norihiko; Jeffrey, Jerry; Foster, Scott A.; Yoshinaga, Tomokazu; Seki, Takahiro; Kobayashi, Masanori; Sato, Akihiko; Johnson, Matthew N; Garvey, Edward P.; Fujiwara, Tamio

doi:10.1021/jm400645w

Cited by 163 publications

(138 citation statements)

References 28 publications

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“…DTG was designed to maintain activity against many INSTI-resistant mutants with single or multiple substitutions (20,(31)(32)(33)(34)(35), and this is consistent with biochemical and structural observations (36,37). Studies showed that the dissociation half-life of DTG from IN/ substrate-DNA/INSTI triple complex in the presence of the amino acid substitutions Q148H, Q148K, or Q148R and N155H significantly reduced the dissociation half-life from that of wildtype IN but was still similar to that of RAL to wild-type IN.…”

Section: Resultsmentioning

confidence: 99%

Effects of Raltegravir or Elvitegravir Resistance Signature Mutations on the Barrier to Dolutegravir Resistance In Vitro

Seki

Suyama-Kagitani

Kawauchi-Miki

et al. 2015

Antimicrob Agents Chemother

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cThe recently approved HIV-1 integrase strand transfer inhibitor (INSTI) dolutegravir (DTG) (S/GSK1349572) has overall advantageous activity when tested in vitro against HIV-1 with raltegravir (RAL) and elvitegravir (EVG) resistance signature mutations. We conducted an in vitro resistance selection study using wild-type HIV-1 and mutants with the E92Q, Y143C, Y143R, Q148H, Q148K, Q148R, and N155H substitutions to assess the DTG in vitro barrier to resistance. No viral replication was observed at concentrations of >32 nM DTG, whereas viral replication was observed at 160 nM RAL or EVG in the mutants. In the Q148H, Q148K, or Q148R mutants, G140S/Q148H, E138K/Q148K, E138K/Q148R, and G140S/Q148R secondary mutations were identified with each INSTI and showed high resistance to RAL or EVG but limited resistance to DTG. E138K and G140S, as secondary substitutions to Q148H, Q148K, or Q148R, were associated with partial recovery in viral infectivity and/or INSTI resistance. In the E92Q, Y143C, Y143R, and N155H mutants, no secondary substitutions were associated with DTG. These in vitro results suggest that DTG has a high barrier to the development of resistance in the presence of RAL or EVG signature mutations other than Q148. One explanation for this high barrier to resistance is that no additional secondary substitution of E92Q, Y143C, Y143R, or N155H simultaneously increased the fold change in 50% effective concentration (EC 50 ) to DTG and infectivity. Although increased DTG resistance via the Q148 pathway and secondary substitutions occurs at low concentrations, a higher starting concentration may reduce or eliminate the development of DTG resistance in this pathway in vitro.

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Section: Resultsmentioning

confidence: 99%

Effects of Raltegravir or Elvitegravir Resistance Signature Mutations on the Barrier to Dolutegravir Resistance In Vitro

Seki

Suyama-Kagitani

Kawauchi-Miki

et al. 2015

Antimicrob Agents Chemother

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“…This flexibility is reminiscent of what is seen with 2 , where the flexibility of the haloamide component is thought to contribute to the ability of 2 to maintain efficacy against certain forms of IN that are resistant to 1 . 18−20 …”

Section: Resultsmentioning

confidence: 99%

4-Amino-1-hydroxy-2-oxo-1,8-naphthyridine-Containing Compounds Having High Potency against Raltegravir-Resistant Integrase Mutants of HIV-1

Zhao¹,

Smith²,

Métifiot

et al. 2014

J. Med. Chem.

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There are currently three HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) approved by the FDA for the treatment of AIDS. However, the emergence of drug-resistant mutants emphasizes the need to develop additional agents that have improved efficacies against the existent resistant mutants. As reported herein, we modified our recently disclosed 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides IN inhibitors to develop compounds that have improved efficacies against recombinant IN in biochemical assays. These new compounds show single-digit nanomolar antiviral potencies against HIV vectors that carry wild-type (WT) IN in a single round replication assay and have improved potency against vectors harboring the major forms of drug resistant IN mutants. These compounds also have low toxicity for cultured cells, which in several cases, results in selectivity indices (CC50/EC50) of greater than 10000. The compounds have the potential, with additional structural modifications, to yield clinical agents that are effective against the known strains of resistant viruses.

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“…They contain a two-metal binding pharmacophore consisting of a carbamoyl pyridone moiety (see Fig. 1) and were optimized to deliver the attributes that would differentiate them as new INSTIs (14,15). Clinical data for GSK1265744 administered to healthy subjects and HIV patients present a PK profile supporting once-daily oral administration from a low-milligram dose, with low PK variability and excellent short-term safety/tolerability, as well as highly effective anti-HIV activity from 10 days of monotherapy (16).…”

mentioning

confidence: 99%

Antiviral Characteristics of GSK1265744, an HIV Integrase Inhibitor Dosed Orally or by Long-Acting Injection

Yoshinaga

Kobayashi

Seki

et al. 2015

Antimicrob Agents Chemother

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GSK1265744 is a new HIV integrase strand transfer inhibitor (INSTI) engineered to deliver efficient antiviral activity with a once-daily, low-milligram dose that does not require a pharmacokinetic booster. The in vitro antiviral profile and mechanism of action of GSK1265744 were established through integrase enzyme assays, resistance passage experiments, and cellular assays with site-directed molecular (SDM) HIV clones resistant to other classes of anti-HIV-1 agents and earlier INSTIs. GSK1265744 inhibited HIV replication with low or subnanomolar efficacy and with a selectivity index of at least 22,000 under the same culture conditions. The protein-adjusted half-maximal inhibitory concentration (PA-EC 50 ) extrapolated to 100% human serum was 102 nM. When the virus was passaged in the presence of GSK1265744, highly resistant mutants with more than a 10-fold change (FC) in EC 50 relative to that of the wild-type were not observed for up to 112 days of culture. GSK1265744 demonstrated activity against SDM clones containing the raltegravir (RAL)-resistant Y143R, Q148K, N155H, and G140S/Q148H signature variants (FC less than 6.1), while these mutants had a high FC in the EC 50 for RAL (11 to >130). Either additive or synergistic effects were observed when GSK1265744 was tested in combination with representative anti-HIV agents, and no antagonistic effects were seen. These findings demonstrate that, similar to dolutegravir, GSK1265744 is differentiated as a new INSTI, having a markedly distinct resistance profile compared with earlier INSTIs, RAL, and elvitegravir (EVG). The collective data set supports further clinical development of GSK1265744.

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Carbamoyl Pyridone HIV-1 Integrase Inhibitors 3. A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and the Discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744)

Cited by 163 publications

References 28 publications

Effects of Raltegravir or Elvitegravir Resistance Signature Mutations on the Barrier to Dolutegravir Resistance In Vitro

Effects of Raltegravir or Elvitegravir Resistance Signature Mutations on the Barrier to Dolutegravir Resistance In Vitro

4-Amino-1-hydroxy-2-oxo-1,8-naphthyridine-Containing Compounds Having High Potency against Raltegravir-Resistant Integrase Mutants of HIV-1

Antiviral Characteristics of GSK1265744, an HIV Integrase Inhibitor Dosed Orally or by Long-Acting Injection

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