Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5613_Библиотеки_им_академика_М_И_Перельмана
.pdf
88
https://t.me/med1917
Chemistry and Pharmacology of Drug Discovery
precursor 16 although it had metabolism issues as well, most likely phase II metabolism
associated with the “naked” amine. Indeed, sulfonylation of 17 gave rise to sulfonamide
18, which was tested to be more robust toward metabolism.
To further enhance the drug’s affinity to the target protein, it was decided to
extend the molecule by making alkynol 19, which further morphed into sulfone 20 (EC
50
= 200 pM). Now the potency of this series of drugs had entered the enviable picomolar
territory. Fine-tuning of sulfone 20, especially at the right-hand portion, led to GS-CA1
(21) as a potential drug candidate. The EC
cytotoxicity concentration was CC
50
of GS-CA1 (21) was 240 pM whereas its
50
> 50 μM, providing a therapeutic window of
>208,300! When administered subcutaneously to a mouse model, one dose of GS-CA1
(21) was able to maintain compound levels above its EC
in the blood plasma for 56
50
days, outperforming the long-lasting NNRTI, rilpivirine (3), in both potency and
selectivity.
13
89
https://t.me/med1917
Obsession to obtain the perfect drug led Gilead to eventually “settling” at
lenacapavir (1) as their drug development candidate. The decision was apparently a wise
one as witnessed by its approval at the end of 2022.
Chapter 4. Lenacapavir (Sunlenca)
In summary, low hepatic clearance is an essential attribute for a long-acting
agent. Thus, along with enhancement of potency, the design process that culminated in
lenacapavir (1) also focused on blocking metabolically labile sites through incorporation
of electron-withdrawing groups (halogens and sulfonyls), metabolically stable ring
systems (cyclopropane and pyrazoles) and rigidifying elements. Many invaluable lessons
in drug design can be learned from this process.
4. Pharmacokinetics and Drug Metabolism
Tritiation of lenacapavir (1) was necessary to accurately measure the low turnover of
lenacapavir (1) in primary human hepatocytes and showed a predicted rate of hepatic
clearance of 0.01/h*kg, or 0.8% of the hepatic extraction.
Not surprisingly, little metabolism was observed for this very robust molecule.
Lenacapavir (1) has a half-life of 7–11 weeks when administered subcutaneously, and it
can be administered orally. It can be used as a long-acting agent for pre-exposure
prophylaxis (PrEP).
3
90
https://t.me/med1917
Chemistry and Pharmacology of Drug Discovery
5. Efficacy and Safety
Lenacapavir (1) has two mechanisms of action at separate stages of the viral life cycle,
thus posing a barrier to resistance that may be intrinsically higher.
The FDA approved lenacapavir
trial in 72 heavily treatment-experienced subjects with multiclass-resistant HIV-1. The
trial met its primary endpoint, with 88% of lenacapavir
of at least 0.5 log10 copies per milliliter in the viral load at day 15, compared with 17%
of placebo recipients.
For long-acting drugs, their safety is of utmost importance because they stay in
the system for over 1 month. Gilead was scrupulous to ensure the safety profile to be
nearly perfect for their drug candidate. Their labor paid off at the end. No serious adverse
events related to lenacapavir
1
(1) were identified in clinical trials.1
(1) on the basis of the phase II/III CAPELLA
(1) recipients having a decrease
6. Synthesis
A synthesis of lenacapavir (1) was published as the supplemental information (SI) of
Gilead’s 2020 Nature article.
may dissect
fragment A, B, and C.
lenacapavir (1) into three simpler and more manageable building blocks:
3
Despite its molecular complexity, a retrosynthetic excise
6.1. Fragment A
Preparation of fragment A commenced with a Simmons–Smith cyclopropanation. Thus,
cyclopent-3-en-1-ol (22) was treated with diethylzinc and diiodomethane to install the
cyclopropane onto 22. Subsequent Dess–Martin periodinane (DMP) oxidation offered
ketone 23. Treatment of ketone 23 with lithium hexamethyldisilazide was followed by
addition of ethyl-trifluoroacetate to generate enolate 24, which was used in situ to react
with ethyl aminoglycinate to forge pyrazole 25. Oxidation of the “benzylic” methylene
91
https://t.me/med1917
Chapter 4. Lenacapavir (Sunlenca)
was accomplished using sodium chlorite and 2-hydroxyisoindoline-dione as co-oxidants
to provide ketone 26, which was then protected as dithiolane 27.
Subsequently, treatment of dithiolane 27 with 1,3-dibromo-5,5dimethylhydantoin (DBDMH, 28) and HF•pyridine converted dithiolane 27 to the
corresponding difluoro-derivative 29. Lithium hydroxide-mediated hydrolysis of the
ethyl ester on 29 revealed carboxylic acid 30. Chiral supercritical fluid chromatography
3
(SFC) separation then delivered fragment A with the desired configuration.
92
https://t.me/med1917
Chemistry and Pharmacology of Drug Discovery
6.2. Fragment B
Preparation of fragment B began with making terminal alkyne 33 by CuCl-mediated
coupling reaction between propargyl chloride 31 and sodium methanesulfinate (32).
Meanwhile, 3,6-dibromo-2-methylpyridine (34) underwent a Wohl–Ziegler
reaction to afford the corresponding “benzyl” bromide, which was subsequently
converted to aldehyde 35 under the influence of silver nitrate. Condensation of aldehyde
35 with Ellman’s chiral auxiliary (S)-sulfinamide 36 gave rise to imine 37, which was
immediately coupled with benzylzinc 38 to assemble adduct 39. Removal of the chiral
auxiliary was carried out using strong acid to expose the “naked” amine 40, which was
protected in situ as the corresponding Boc derivative 41. A Sonogashira coupling reaction
between terminal alkyne 33 with 41 chemoselectively took place with the α-bromide to
install fragment B. For the two bromides on pyridine 41, the α-bromide is exponentially
more reactive than the γ-bromide because the α-bromide is activated by the neighboring
nitrogen atom.
93
https://t.me/med1917
Chapter 4. Lenacapavir (Sunlenca)
6.3. Fragment C
Production of fragment C employed 1-bromo-4-chloro-2-fluorobenzene (42) as the
starting material. Deprotonation of 42 with lithium diisopropylamide took place
selectively at the most acidic C-3 position. Quenching the anion with DMF provided the
corresponding aldehyde, which was promptly coupled with sulfamic acid
(hydroxylamine-O-sulfonic acid), and the adduct immediately collapsed to offer nitrile
43. Heating nitrile 43 with hydrazine hydrate in ethanol gave the S
replacing the fluorine. The adduct then simultaneously underwent an intramolecular
cyclization to afford aminoindazole 44. Alkylation of aminoindazole 44 selectively
attached the trifluorethyl group at the most acidic 1H position to prepare 45. A Miyaura
coupling of 45 with bis(pinacolato)diboron then delivered fragment C as a boronate.
Ar adduct by
N
6.4. Assembly of Lenacapavir (1)
The final assembly of lenacapavir (1) began with a Suzuki coupling between the bromide
on fragment B with the boronate on fragment C to produce adduct 47. Sulfonylation of 47
94
https://t.me/med1917
with mesyl chloride could not stop at the mono-sulfonylation stage, giving rise to bissulfonamide 48. Removal of the Boc protection on 48 with trifluoroacetic acid exposed
the primary amine on 49, which was then coupled with fragment A using HATU as the
coupling agent. Treatment of the adduct with sodium hydroxide then removed one of the
two sulfonamides to deliver lenacapavir (1).
Chemistry and Pharmacology of Drug Discovery
It is likely that the process and commercial routes are even more efficient than
the current one.
95
https://t.me/med1917
Chapter 4. Lenacapavir (Sunlenca)
7. Summary
We have come a long way on the road to conquest HIV, the invisible enemy.
Impressively, nearly half of all antiviral drugs on the market are used for the treatments
of AIDS. The other class of major antiviral drugs are anti-hepatitis C virus (HCV) drugs.
The lessons that we learned from our war against HIV/AIDS and HCV have greatly aided
our endeavor on discovering drugs to treat SARS-CoV-2.
Long-acting HIV drugs are at the frontier of the AIDS field. Now with the
availability of lenacapavir (1), patient compliance will be greatly improved now that it
only needs to be given twice a year. PrEP is another significant advantage of this drug.
As we advance the field of antiviral drugs against HIV, it is not a stretch of
imagination that 1 day when eradication of this once deadly disease becomes a reality!
References
1. Mullard, A. FDA approves first-in-class HIV capsid inhibitor. Nat. Rev.
Drug Discovery 2023, 22, 90.
2. Orkin, C. Lenacapavir in first-line therapy. Lancet HIV 2023, 10, e2–
e3.
3. Link, J. O.; Rhee, M. S.; Tse, W. C.; Zheng, J.; Somoza, J. R.; Rowe,
W.; Begley, R.; Chiu, A.; Mulato, A.; Hansen, D.; et al. Clinical
targeting of HIV capsid protein with a long-acting small molecule.
Nature 2020, 584, 614−618.
4. Zhang, X.; Sun, L.; Xu, S.; Shao, X.; Li, Z.; Ding, D.; Jiang, X.; Zhao,
S.; Cocklin, S.; Clercq, E. D.; et al. Design, synthesis, and mechanistic
study of 2-pyridone-bearing phenylalanine derivatives as novel HIV
capsid modulators. Mol. Ther. 2022, 27, 7640.
5. Momany, C.; Kovari, L.; Prongay, A.; Keller, W.; Gitti, R.; Lee, B.;
Gorbalenya, A.; Tong, L.; McClure, J.; Ehrlich, L.; Summers, M.;
Carter, C.; Rossmann, M. Crystal structure of dimeric HIV-1 capsid
protein. Nat. Struct. Biol. 1996, 3, 763−770.
6. Zhuang, S.; Torbett, B. E. Interactions of HIV-1 capsid with host
factors and their implications for developing novel therapeutics.
Viruses 2021, 14, 417.
7. McFadden, W. M.; Snyder, A. A.; Kirby, K. A.; Tedbury, P. R.; Raj,
M.; Wang, Z.; Sarafianos, S. G. Rotten to the core: antivirals targeting
the HIV-1 capsid core. Retrovirology 2021, 18, 41.
8. Freed, E. O. HIV-1 assembly, release and maturation. Nat. Rev.
Microbiol. 2015, 13, 484−496.
96
https://t.me/med1917
9. Zhang, X.; Xu, S.; Sun, L.; Ding, D.; Tao, Y.; Kang, D.; Liu, X.; Zhan,
10. Blair, W. S.; Pickford, C.; Irving, S. L.; Brown, D. G.; Anderson, M.;
11. Sun, L.; Zhang, X.; Xu, S.; Huang, T.; Song, S.; Cherukupalli, S.;
12. Gillis, E. P.; Parcella, K.; Bowsher, M.; Cook, J. H.; Iwuagwu, C.;
13. Yant, S. R.; Mulato, A.; Hansen, D.; Tse, W. C.; Niedziela-Majka, A.;
Chemistry and Pharmacology of Drug Discovery
P. HIV-1 capsid inhibitors: a sword to destroy the virus. Future Med.
Chem. 2022, 14, 605−607.
Bazin, R.; Cao, J.; Ciaramella, G.; Isaacson, J.; Jackson, L.; et al. HIV
capsid is a tractable target for small molecule therapeutic intervention.
PLoS Pathog. 2010, 6, e1001220.
Zhan, P.; Liu, X. An insight on medicinal aspects of novel HIV-1
capsid protein inhibitors. Eur. J. Med. Chem. 2021, 217, 113380.
Naidu, B. N.; Patel, Manoj; Peese, K.; Huang, H.; Valera, L.; et al.
Potent long-acting inhibitors targeting the HIV-1 capsid based on a
versatile quinazolin-4-one scaffold. J. Med. Chem. 2023, 66,
1941−1954.
Zhang, J. R.; Stepan, G. J.; Jin, D.; Wong, M. H.; Perreira, J. M.;
Singer, E. A highly potent long-acting small-molecule HIV-1 capsid
inhibitor with efficacy in a humanized mouse model. Nat. Med. 2019,
25, 1377–1384.
5
https://t.me/med1917
________________________________________________________________________________
Fostemsavir (Rukobia): An HIV-1 gp120-
Directed Attachment Inhibitor for Treating
AIDS
Tao Wang and
Xiang Li
1. Background
Since the start of the AIDS outbreak four decades ago, HIV-1 has infected roughly 84
million people worldwide and caused the deaths of approximately 40 million
individuals.
secretions. If left untreated, HIV-1 can progress to AIDS, which can prove fatal for adults
within 2–10 years. Infants who are infected during gestation, perinatal or lactation period
via vertical transmission experience rapid disease progression, resulting in a 50%
mortality rate within 24 months.
Chemistry and Pharmacology of Drug Discovery, First Edition. Edited by Jie Jack Li.
© 2025 John Wiley & Sons, Inc. Published 2025 by John Wiley & Sons, Inc.
1
The virus is spread through bodily fluids, including blood and genital
2
Соседние файлы в папке Библиотека им академика М.И. Перельмана