Design, synthesis and SAR study of bridged tricyclic pyrimidinone carboxamides as HIV-1 integrase inhibitors.

The design, synthesis and structure-activity relationships associated with a series of bridged tricyclic pyrimidinone carboxamides as potent inhibitors of HIV-1 integrase strand transfer are described. Structural modifications to these molecules were made in order to examine the effect on potency towards wild-type and clinically-relevant resistant viruses. The [3.2.2]-bridged tricyclic system was identified as an advantageous chemotype, with representatives exhibiting excellent antiviral activity against both wild-type viruses and the G140S/Q148H resistant virus that arises in response to therapy with raltegravir and elvitegravir.

The discovery and preclinical evaluation of BMS-707035, a potent HIV-1 integrase strand transfer inhibitor.

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.

Synthesis and evaluation of C2-carbon-linked heterocyclic-5-hydroxy-6-oxo-dihydropyrimidine-4-carboxamides as HIV-1 integrase inhibitors.

Integration of viral DNA into the host cell genome is an obligatory process for successful replication of HIV-1. Integrase catalyzes the insertion of viral DNA into the target DNA and is a validated target for drug discovery. Herein, we report the synthesis, antiviral activity and pharmacokinetic profiles of several C2-carbon-linked heterocyclic pyrimidinone-4-carboxamides that inhibit the strand transfer step of the integration process.

Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge.

Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.