Picomolar inhibitor of reverse transcriptase featuring significantly improved metabolic stability

Considering the undesirable metabolic stability of our recently identified NNRTI 5 (t1/2 = 96 min) in human liver microsomes, we directed our efforts to improve its metabolic stability by introducing a new favorable hydroxymethyl side chain to the C-5 position of pyrimidine. This strategy provided a series of novel methylol-biphenyl-diarylpyrimidines with excellent anti-HIV-1 activity. The best compound 9g was endowed with remarkably improved metabolic stability in human liver microsomes (t1/2 = 2754 min), which was about 29-fold longer than that of 5 (t1/2 = 96 min). This compound conferred picomolar inhibition of WT HIV-1 (EC50 = 0.9 nmol/L) and low nanomolar activity against five clinically drug-resistant mutant strains. It maintained particularly low cytotoxicity (CC50 = 264 μmol/L) and good selectivity (SI = 256,438). Molecular docking studies revealed that compound 9g exhibited a more stable conformation than 5 due to the newly constructed hydrogen bond of the hydroxymethyl group with E138. Also, compound 9g was characterized by good safety profiles. It displayed no apparent inhibition of CYP enzymes and hERG. The acute toxicity assay did not cause death and pathological damage in mice at a single dose of 2 g/kg. These findings paved the way for the discovery and development of new-generation anti-HIV-1 drugs.

Development of fluorine-substituted NH2-biphenyl-diarylpyrimidines as highly potent non-nucleoside reverse transcriptase inhibitors: Boosting the safety and metabolic stability

Our recent studies for nonnucleoside reverse transcriptase inhibitors identified a highly potent compound JK-4b against WT HIV-1 (EC50 = 1.0 nmol/L), but the poor metabolic stability in human liver microsomes (t 1/2 = 14.6 min) and insufficient selectivity (SI = 2059) with high cytotoxicity (CC50 = 2.08 μmol/L) remained major issues associated with JK-4b. The present efforts were devoted to the introduction of fluorine into the biphenyl ring of JK-4b, leading to the discovery of a novel series of fluorine-substituted NH2-biphenyl-diarylpyrimidines with noticeable inhibitory activity toward WT HIV-1 strain (EC50 = 1.8-349 nmol/L). The best compound 5t in this collection (EC50 = 1.8 nmol/L, CC50 = 117 μmol/L) was 32-fold in selectivity (SI = 66,443) compared to JK-4b and showed remarkable potency toward clinically multiple mutant strains, such as L100I, K103N, E138K, and Y181C. The metabolic stability of 5t was also significantly improved (t 1/2 = 74.52 min), approximately 5-fold higher than JK-4b in human liver microsomes (t 1/2 = 14.6 min). Also, 5t possessed good stability in both human and monkey plasma. No significant in vitro inhibition effect toward CYP enzyme and hERG was observed. The single-dose acute toxicity test did not induce mice death or obvious pathological damage. These findings pave the way for further development of 5t as a drug candidate.

A study of profile of patients failing first line NACO recommended ART

Background: Failure of first line NACO recommended Therapy has been reported in 1-5% cases of HIV/AIDS. Various factors are associated with failure. This study describes the profile of patients failing first line ART (FLA) in a predominately lower socioeconomic population. The objective of the present study was to identify factors associated with failure of FLA.Methods: Retrospective data analysis of patients failing first line therapy. Epidemiological information, clinical parameters and laboratory reports were taken into consideration. Data was analysed as per standard statistical analysis.Results: Out of a total 3926 patients on first line ART for varying periods of time from our ART centre 54 patients were on second line ART. Males (2.20%) had a high failure rate than females (0.50%). The average time of failure was 64.11 months with a median of 56.50 months. 74.1% (40/54) of the patients had very low CD4 count at the time of initial diagnosis. Failure rate of FLA was higher in the patients having Stavudine based regimen (NRTI) (6.61%) and 3.64% in patients having Nevirapine based regimen (NNRTI).Conclusions: Second line therapy is required only in a small number of patients at present, but as it is related to the duration on first line ART and also with initial low CD4 count, more and more patients will require SLA in the near future.

Individualization of antiretroviral therapy - Pharmacogenomic aspect.

Combination therapy with three drug regimens for human immunodeficiency virus (HIV) infection significantly suppresses the viral replication. However, this therapeutic impact is restricted by adverse drug events and response in terms of short and long term efficacy. There are multiple factors involved in different responses to antiretrovirals (ARVs) such as age, body weight, disease status, diet and heredity. Pharmacogenomics deals with individual genetic make-up and its role in drug efficacy and toxicity. In depth genetic research has provided evidence to predict the risk of developing certain toxicities for which personalized screening and surveillance protocols may be developed to prevent side effects. Here we describe the use of pharmacogenomics for optimal use of HAART (highly active antiretroviral therapy).

Clinical pharmacology and pharmacokinetics of antiretrovirals in Asia

Pharmacokinetics can be used to establish dose response relationships in terms of efficacy and toxicity. Nevertheless the majority of the registered dose in the treatment of HIV are based on data from Caucasian men. It is questionable however if the recommended doses are optimal for all ethnicities and in all circiumstances. Several studies suggest that a more population-based approach may benefit different ethnicities. Here we review the pharmacokinetics of commonly used non-nucleoside analog reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) in the Asian setting, for both adults and children. Studies of nevirapine, efavirenz, saquinavir, lopinavir, ritonavir, indinavir and atazanavir have been reported mostly among Thai patients. The data strongly indicated that Thai and most likely Asians have on average a significantly higher exposure to both the drugs classes (NNRTIs and PIs) compared to the Caucasian. In patients with active tuberculosis who are taking rifampicin, the standard dose of either efavirenz or nevirapine was found to be sufficient and efficacious for Asians with average body weight of 60 kg. Lower dose studies of saquinavir, indinavir, lopinavir and atazanaivr have shown promising efficacy results, however most are small scale studies. In pregnancy, nevirapine seems an adequate option whereas efavirenz has no PK data during the third trimester. In conclusion, more likely Asians are significantly higher exposed to both NNRTIs and PIs compared to the Caucasians. Further studies on pharmacokinetics, TDM and larger scale clinical trials among Asian populations are warranted to identify suitable low doses of ARVs for mclusion in the clinical practice guidelines of this region.