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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5371_Библиотеки_им_академика_М_И_Перельмана
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Chemistry and Pharmacology of Drug Discovery
was developed first. The methyl derivative 1 performed best within the five-membered
ring series when potency, protein shift, and mutant profile were all considered. Therefore,
it was not surprising that it was chosen as a drug candidate that ultimately became
12
cabotegravir (1).
4. Pharmacokinetics and Drug Metabolism
Preclinical pharmacokinetic parameters in Sprague−Dawley rats, beagle dogs, and
12
2.
cynomolgus monkeys for 14 and 1 are shown in Table
Both dolutegravir (14) and cabotegravir (1) are highly protein-bound (>99%).
Cabotegravir (1) had a large protein shift (60-fold) in the presence of human serum
albumin (HAS), however, again this was attenuated by its intrinsic potency and the high
protein binding may have a favorable impact on pharmacokinetic properties (for example,
increasing half-life).
12
When administered as a LAI formulation, cabotegravir (1) exhibits an extremely
long half-life of approximately 21–50 days. This prolonged half-life is a result of the poor
solubility of the nanoparticles in tissue, which allows for a slow absorption rate as
opposed to decreased plasma elimination. Cabotegravir (1) possesses a number of
properties that favorably lend it to formulation as a LAI, including slow metabolism, a
18
high melting point and low aqueous solubility.
Table 2. Preclinical pharmacokinetic parameters for 14 and 1
Compound Species
Cl (mL/min/kg) T
(h) V
1/2
(L/kg) %F
dss
14 Rat 0.23 6.2 0.1 34
1 Rat NR > 18 NR NR
14 Dog 2.2 5.2 0.3 35
1 Dog 0.34 5.7 0.14 8
14 Cyno 2.1 6.0 0.3 25
1 Cyno 0.32 4.0 0.09 6.2
Another advantage of cabotegravir (1) relies on its main metabolization by
uridine diphosphate glucuronosyl-transferase 1A1, leading to less likely interactions with
other antiretroviral drugs. To a lesser extent, cabotegravir (1) is metabolized hepatically
by UGT1A9. It is a mild inhibitor of organic anion transporter (OAT) 1 and OAT3 and
does not have any significant impact on cytochrome P450 or other UGT enzymes based
3
on cabotegravir (1) plasma levels obtained from standard doses.
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Chapter 3. Cabotegravir (Vocabria)
5. Efficacy and Safety
Cabotegravir (1) is significantly higher than that of dolutegravir (14) were discovered by
evaluation of
inhibitor-resistant mutants,
profiles included a key measure of the trough drug concentration over protein-adjusted
antiviral potency (PAIC
demonstrated good coverage over PAIC50 predicting low mg unboosted once daily
dosing, now validated in clinical studies. These preclinical data along with a long human
T
of ~30 h in oral tablet study supports cabotegravir (1) as a long acting parenteral
1/2
agent for once-monthly or less frequent dosing.
Compound
1 3.0 1.3 0.2 408 166
14 2.7 2.0 0.5 75 64
Table
addition, their cellular activities were tested in both MT4 cell and peripheral blood
mononuclear cell (PBMC) HIV multi-round replication assays. The fold shift (408×) for
cabotegravir (1) is significantly higher than that of dolutegravir (14, 75×) when they were
tested in the presence of human serum albumin (HSA). As a consequence, the PAIC
value for cabotegravir (1) is higher than that of dolutegravir (14).12
was given intramuscularly
infection. The combination drug was found to be
therapy of cabotegravir
suppression through 96 weeks and was well accepted and tolerated.
two-drug combination in place of the old three-drug combination, simplifying the
treatment regimens.
headache.
antiviral activity against wild-type virus (±HSA) along with key integrase
Q148K as the most important one. Animal pharmacokinetic
) along with in vitro DMPK properties. Cabotegravir (1)
50
Table 3. Virological profile of cabotegravir (1) and dolutegravir (14)
INST IC
(nM)
4
50
MT
IC
50
(nM)
PBMC
(nM)
IC
50
100% HuS
fold shift
PAIC
90
(ng/mL)
The virological profile of cabotegravir (1) and dolutegravir (14) are shown in
3. The biochemical assay was used to measure the potency against INST. In
90
A phase 2b clinical trial, a combination of cabotegravir (1) and rilpivirine (2)
every 4 weeks or every 8 weeks to adults with HIV-1
as effective as daily three-drug oral
(1) plus abacavir–lamivudine at maintaining HIV-1 viral
Thanks to their superb efficacy, cabotegravir (1) and dolutegravir (14) allow
Common adverse effects include injection site reactions, pyrexia, fatigue, and
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Chemistry and Pharmacology of Drug Discovery
6. Synthesis
6.1. Discovery Route
The discovery route to make cabotegravir (1) was lengthy but straightforward.
Maltol (33) was protected as benzylether 34, which was converted to pyridone
35 using ammonia with the aid of NaOH. Regioselective bromination of pyridone 35 with
N-bromo-succinimide (NBS) afforded 5-bromo-pyridone 36, which was readily
transformed to the corresponding ester 37 via a palladium-catalyzed carbonylation.
Acetylation of 37 led to aromatization product pyridine 38, which was oxidized to the
corresponding pyridine-oxide 39 using m-CPBA. The Boekelheide reaction was then
carried out by treating pyridine-oxide 39 with acetic anhydride at high temperature to
give acetoxymethylpyridine 40. Selective removal of the two acetates was achieved by
treating 40 with sodium methoxide in methanol to reveal pyridone 41, sparing the methyl
ester. Heating 41 with 2,4-difluorobenzylamine assembled amide 42, which was oxidized
by manganese dioxide and sulfamic acid sequentially to provide acid 43. Esterification of
acid 43 with methanol was accomplished using EDAC as the coupling agent in refluxing
DMF to produce the key intermediate 44.
11
11,12
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Chapter 3. Cabotegravir (Vocabria)
N-Allylation of pyridone 44 with allylbromide prepared terminal olefin 45.
Rather than using the dangerous ozonolysis conditions, olefin 45 was treated with sodium
metaperiodate employing osmium tetraoxide (in the form of potassium osmate dihydrate)
11
as the catalyst to make aldehyde 46.
aminopropan-1-ol was catalyzed by acetic acid to deliver
palladium-catalyzed debenzylation. The condensation gave rise to
stunning 40:1 diastereomeric ratio (dr).
Finally, condensation of aldehyde 46 with (S)-2-
cabotegravir (1) after
cabotegravir (1) in a
12
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Chemistry and Pharmacology of Drug Discovery
6.2. Process Route
GSK Process Chemistry group published a one-pot, four-step route to pyridone 51.
Condensation of β-ketoester 47 with neat DMF-DMA produced vinylogous
dimethyl amide 48, which was condensed in situ with aminoacetaldehyde dimethyl acetal
in methanol to assemble vinylogous amide 49. Without workup or isolation, vinylogous
amide 49 was coupled with dimethyl oxalate and LiOMe in MeOH to promote the
formation of pyridone 50, which was selectively (10:1) hydrolyzed to mono-acidic
pyridone 51. In contrast, NaOH and KOH only gave a 3:1 selectivity.
20
20–22
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Chapter 3. Cabotegravir (Vocabria)
Removal of the acetal protection was facilitated by catalytic methanesulfonic
acid in acetic acid and acetonitrile to reveal aldehyde 52, which was condensed in situ
with (S)-2-aminopropan-1-ol to install tricyclic pyridone acid 53 in 34:1 dr. It was
activated with CDI and then coupled with 2,4-difluorobenzylamine to afford amide 54.
At the end, demethylation of 54 was accomplished using LiBr to deliver
cabotegravir
(1).20
6.3. An Alternative Route
GSK Process Chemistry also disclosed an alternative route to make cabotegravir (1).
Alternatively, amide formation was carried out before removal of the acetal
protection. Thus, acid 51 was activated with CDI and then coupled with 2,4difluorobenzylamine to afford amide 55. Formic acid-promoted deprotection revealed
aldehyde 56, which was coupled with (S)-2-aminopropan-1-ol to deliver
after demethylation.
It is poetic justice when a magnesium salt Mg(OTf)
condensation reaction to make a drug that works by chelating also to magnesium divalent
ions!
21,22
cabotegravir (1)
21
was used to carried out the
2
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Chemistry and Pharmacology of Drug Discovery
7. Summary
Cabotegravir (1) and doletegravir (14) are obtained by extensive SAR investigation from
the monocyclic carbamoyl pyridones. While retaining the magnesium ion chelating
functionalities, the Shionogi/GSK team discovered that the tricyclic derivatives endowed
the carbamoyl pyridones with preferable DMPK profile for long-acting inhibition.
Factors contributing to cabotegravir (1)’s long half-life include low water solubility, high
activity, long half-life, and slow metabolic clearance.
Another advantage of cabotegravir (1) relies on its main metabolization by
uridine diphosphate glucuronosyl-transferase 1A1, leading to less likely interactions with
other antiretroviral drugs. The drug adds a powerful weapon in the arsenal for our war
against HIV/AIDS.
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WO2011119566 (2011), Sep 29, 2011.
Lenacapavir (Sunlenca): A Long-acting HIV-
https://t.me/med1917
1 Capsid Protein Inhibitor for Treating HIV
Infection
Jie Jack Li
4
At the end of 2022, the FDA approved Gilead’s long-acting human immunodeficiency
virus-1 (HIV-1) drug lenacapavir (1, Sunlenca), a first-in-class HIV capsid protein
inhibitor, providing a new treatment option for people suffering from multidrug
resistance.
a. It is really long acting, only needs to be given two injections a year;
b. It can be used as pre-exposure prophylaxis (PrEP);
c. It is a first-in-class HIV-1 capsid protein inhibitor;
d. Its molecular weight is 968, way beyond the rule-of-5; and
e. It has 10 fluorine atoms, a record previously held by Merck’s aprepitant
(Emend) with “merely” seven fluorine atoms.
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, 2
Several aspects about lenacapavir (1) are truly remarkable:
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