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Etravirine:20 Years of
Research on Non-
Nucleoside Inhibitors of
HIV-1 Reverse
Transcriptase
Introduction to HIV
• The 20th century had faced two unexpected viral
outbreaks.
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HIV Life Cycle
http://img.thebody.com/nmai/cycle.jpg
Drug development-Making
Strategies
• One strategy is to destroy or repair the affected genes in human
T-cells.
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Antiretroviral Drug
Classes
• Depending upon their way of action these
drugs can be classified in following groups,
• Nucleoside/Nucleotide Reverse
Transcriptase Inhibitors (NRTIs)
• Non-Nucleoside Reverse Transcriptase
Inhibitors (NNRTIs
• Protease Inhibitors (PIs)
• Fusion or Entry Inhibitors
• Integrase Inhibitors
• Maturation inhibitors
History Begins
• Etrvirine a brand new drag which got the
FDA approval in January 2008
• The drug was marketed by Tibotec
Therapeutics, a subsidiary of
Johnson & Johnson
• Research work started in the year of 1987
at Janssen Pharmaceutica and under the
guidance of legendary Dr.Paul Janssen
Discovery of TIBO and αAPA Series: The
O
Cl O Br H3C H
N
H
N
NH
N Br NH NH NH
S O NH2
• The researchers did an extensive SAR on α-APA series and came out
with some promising results (Table-1)
Table.1.Activity (EC50,µm) O Cl
Cl H
Compound E Y EC50(µM)
H Y N
4a CH2 o-NO2 >50 N
E
4b CO o-NO2 >50 Cl
4c CONH o-NO2 >50 Cl H2N O
O NH2
4d CSNH o-Cl >50
4e CSNH p-Cl 0.10 (4) Lov iride(5)
4f - o-Cl 0.4
• They noticed in general increasing the spacer length between two aryl
groups in loviride result in considerable decrease in activity
• But 4e which was surprisingly active compared to all other analogues
Discovery of Imidoyl Thioureas (ITUs) series:
potent 2nd line of NNRTIs
(6)
Drawback of R100943
• The in vitro activity profile of ITU-R100943 vs HIV-1 (Table2.)
justified the consideration of it for clinical development
• But unfortunately the oxidative ring closure of the imidoyl thiourea
functionality, under metablolic condition proved to be a major liability
for this drug candidate as the cyclic thiadiazole derivative(7)
resulting from metabolic oxidation was inactive (EC50>1µM vs HIV-1)
N N
Oxidation
Cl Cl Cl Cl
N NH N NH
NH S N S
R100943 (7)
Information obtained 2nd Series of
NNRTIs
• Crystal structure of RT\R100943 complex revealed that the
conformation of the inhibitor at NNIBP resembles a ‘U’ or
horseshoe shape (Fig.3) in contrast to butterfly shape as in the
case of TIBO or α-APA derivatives.
Discovery of Diaryltrazine(DATA) 3rd Series
NNRTIs
• The key design features learned from the study of
ITU derivatives are,
(1)The horseshoe binding mode must be maintained in
the succeeding drug candidates
Cl Cl
N N H
Cl Cl + H
Cl Cl
O N N N
N H H
2 N N H
N N H
N H C N C N 2
N H N
N C
(9)
(8)
(8) (9)
Table.3.Activity
Table.3 of DATAs
Comp. R Y LAI(HIV-1) L100I K103N R
10
10c 2,6-di-Me-4-CN NH 0.001 0.25 0.008
(10)
Drawbacks DATA Series of
Derivatives
N N
Cl Cl
Cl Cl Cl Cl
N NH
N NH NH
N
N N N
NH 2 NH2
NH 2
O N NH HN N NH O N NH
HN N NH
N N N
N
12b 12c 12d
12a
Table.4.Activity(EC50,µM) of 12a-d
Comp. LAI(HIV-1) L100I K103N L100I+K103N K103N+Y181C
Table.5.Activity(EC50,µM) of 13a-c
Y N NH
Comp R Y LAI(HIV-1) L100I K103N Y181C L100I+K103N K103N+Y181C
N
Br
13a Me NH 0.006 0.011 0.007 0.036 0.35 0.28
O N NH
N
Br
NH2
Etravirine
Table.6.Activity(EC50,µM) of Etravirine
Color codes: orange, EC50 > 0.1 µM; yellow, 0.1 > EC50 > 0.01 µM; and light yellow, EC50 < 0.01 µM.
Activity of Etravirine
• But the potency of etravirine against the double mutants
L100I+K103N and K103N+Y181C (Table.7) makes it as an extraordinary
drug candidate.
N N
Table.7.
Comp. L100I+K103N K103N+Y181C
Nevirapine nb >10
Delaviridine nb >10
HN N NH
Ralpivirine
Conclusion
• Though so many effective HIV anti-
retrovirals are available most of them
are very expensive and only rich people
can afford those medication
• Research should be continued to find
out effective drugs which will be
cheaper and accessible to all.
References
1. Bart L De Corte,J.Med. Chem. 2005,48,1689-1696
4. Web Sources-www.wikipedia.org
Thank you and have a
nice day