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Chemistry and Pharmacology of Drug Discovery
Meanwhile, a streamlined synthesis of triazolinone 40 was developed. To that
end, treating phenyl chloroformate with aqueous methylamine prepared carbamate 36.
Semicarbazide 37 was generated by the addition of hydrazine in hot 2-propanol to
carbamate 36 and converted without isolation to acylated adduct 38 in 81% yield over the
two steps. Based-catalyzed cyclization furnished triazolinone-alcohol 39, which was
28
converted to triazolinone chloride 40.
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Chapter 2. Doravirine (Pifeltro)
Eventually, doravirine (1) was assembled using an optimized SN2 reaction
between pyridone 30 and chloride 40.
28
7. Summary
Although their own HTS hits did not offer viable leads, Merck did not shy away from a
competitor’s
smart drug design of novel bioisosteres. Pyridone as the core structure was not only novel
but also possessed superior physiochemical properties in comparison to the original
diarylether.
Another laudable achievement of drug design was finding the monocyclic
methyl-triazolone as the sidechain in place of bicyclic pyrazolopyridine. It overcame the
intermolecular hydrogen bonding issue associated with pyrazolopyridine to boost the
solubility. Moreover, a smaller molecule
physiochemical properties than the bicyclic analogues.
Finally, employing the state-of-the-art flow chemistry has contributed to the
success of the robust manufacturing process.
compound. The trick was to achieve novel intellectual properties through
doravirine (1) is likely to have better
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Chapter 2. Doravirine (Pifeltro)
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________________________________________________________________________________
Cabotegravir (Vocabria): An HIV Integrase
Strand Transfer Inhibitor for Treating HIV
Infection
Jie Jack Li
Long-acting HIV/AIDS treatments are a great boon for patient compliance. At the end of
2022, the FDA approved Gilead’s long-acting lenacapavir (Sunlenca), an HIV-1 capsid
protein inhibitor. Only injections are given twice a year and lenacapavir can be used as
pre-exposure prophylaxis (PrEP).
Before the approval of lenacapavir, Cabenuva was the only long-acting HIV
drug on the market. Approved in January 2021 by the FDA for treating HIV infection,
Cabenuva is an extended release injectable suspension of cabotegravir (1) and rilpivirine
(2), given once every other month. Cabotegravir (1), the focus of this chapter, is an HIV
integrase strand transfer inhibitor (INSTi) with a remarkable long half-life of
approximately 50 days, whereas rilpivirine (2) is a second-generation nonnucleoside
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.
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reverse transcriptase inhibitor (NNRTI).
approved as the first long-acting injectable (LAI) for HIV PrEP.
originated by Shionogi/GSK and developed by Viiv Healthcare, a specialized HIV
company established in late 2009 by GSK and Pfizer.
The availability of highly potent antiretrovirals such as cabotegravir (1) with
high barriers to resistance has made dual therapy, rather than the traditional triple
therapy, a reality for many patients.
Chemistry and Pharmacology of Drug Discovery
1,2
Cabotegravir (1, Vocabria) has now also been
3
Cabotegravir (1) is
1. Background
We have come a long way in combating the invisible enemy HIV-1 since the early 1980s.
With more than 25 FDA-approved drugs, the infection has been transformed from a death
sentence to a chronic disease that can be managed using effective combination
antiretroviral therapies (cARTs). One area that we are still struggling is vaccine. No safe
and efficacious HIV/AIDS vaccine has emerged even though many intelligent and
diligent scientists have been working on it for decades.
In Chapter 2 on Merck’s doravirine, an NNRTI, I already summarized the
landscape of HIV antiretroviral drugs. Here, we directly jump into the pharmacology of
HIV integrase inhibitors.
2. Pharmacology
Like other INSTIs, cabotegravir (1) exerts its mechanism of action (MoA) by blocking
integrase, an enzyme involved in inserting HIV’s viral DNA into the host cellular DNA.
Let us look at the drug target, HIV integrase.
2.1. HIV Integrase
HIV is a retrovirus that encodes 15 proteins, of which only three have enzymatic
activities: integrase, protease, and reverse transcriptase.
2.1.1. Functions of HIV Integrase
HIV integrase catalyzes the insertion of viral DNA produced by the retro-transcription
process into the genome (host DNA) of the infected human cell. This process is an
essential step in the HIV viral life cycle and the key step in establishing a permanent
infection. HIV integrase is an attractive target because there is no cellular homologue in
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human thus integrase inhibitors offer selectivity and less chances of drug resistance. The
in vivo integration process of viral DNA into host DNA is depicted in Figure
Chapter 3. Cabotegravir (Vocabria)
1.
Following reverse transcription, viral DNA is primed for integration in the
cytoplasm by the integrase-mediated cleavage (a hydrolysis step) of two nucleosides
Figure 1. The in vivo integration process
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Chemistry and Pharmacology of Drug Discovery
from its 3′-ends, which is referred to as 3′-processing. At this point, the integrase remains
bound to the viral DNA as a multimeric complex. The complex is referred to as a preintegration complex (PIC) that bridges both ends of the viral DNA. Subsequently, the
PIC migrates from cytoplasm to nucleus, where the viral DNA undergoes strand transfer
followed by 5′-processing, a transesterification step. The result is fusion of the viral DNA
into the host DNA, giving rise to integrated genome.
4
As mentioned before, the integration process involves two integrase catalytic
reactions: 3′-processing and strand transfer. Both reactions are catalyzed by two highly
cooperative divalent cations centered on a phosphodiester bond. The integration process
can be divided into several stages as shown in Figure
2. Stage A is when the integrase
recognizes the adenine base conserved in the third position from 3′-end of viral DNA.
then activates the next phosphoric ester with the two metals (Stage B to C). Stage A–C
indicates the 3′-processing reaction performed in the cytoplasm. After 3′-processing, the
HIV-1 PIC enters the nucleus, where integrase catalyzes the insertion of the viral DNA
ends into the host chromosome.
5
Figure 2. The two-metal-ion catalysis and inhibition mechanism. Source: Reproduced
Once in the nucleus, the activated phosphoryl ester is hydrolyzed to excise the
terminal dinucleotide and the recognized adenosine is exposed as the new 3′-end, giving a
PIC (Stage C to D). The PIC nonspecifically binds to host DNA to activate a phosphoryl
ester by the two metals (Stage D to E). The activated phosphoric ester is attacked by the
recessed 3′-end in the manner of S
with permission Kiyama et al.
2-like nucleophilic reaction, then the viral DNA and
N
5
, Elsevier
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Chapter 3. Cabotegravir (Vocabria)
the host DNA are joined with each other. An inhibitor chelates to the two metal ions of
Stage C to block the host DNA binding (Stage X). Stage C–E represents the strand
transfer reaction performed in nucleus.
5
Of course, the reality is much more complicated and nuanced. The mechanisms
do not really take place sequntially and stage-wise. In fact, some steps can happen
simultaneously.
2.1.2. The Structure of HIV Integrase
HIV integrase is associated with poly-nucleotidyl transferases superfamily of enzymes. It
consists of 288 amino acids with a molecular weight of 30 KDa. In order to carry out the
3′-processing reaction, an integrase dimeric configuration is required. On the other hand,
an integrase tetrameric configuration is needed for catalyzing the subsequent strand
transfer.
Integrase’s N-terminal domain (NTD) contains 50 amino acids and has the
HHCC zinc-finger that binds to zinc ion (Figure
because it contains 4 conserved residues in the form of 2 histidine (H12 and H16) and 2
cysteine (C40 and C43). The catalytic core domain (CCD) containing amino acids 51–
211 is where the action is. Binding to Mn
protein. It contains DDE motif that makes up the active site triad, also known as the
catalytic triad with two aspartates (D64 and D116) and one glutamine (E152). The Cterminal domain (CTD) contains amino acids 212–288. It binds nonspecifically with the
DNA and its linkage with CCD is essential for 3′-processing and strand transfer
activities.
6
3). The HHCC zinc-finger is so-named
++
or Mg++, the CCD is the enzymatic core of
Figure 3. HIV integrase structural domains. Source: Adapted from Gill et al. 6
Because integrase enzyme catalyzes HIV integrase inhibitors are also known as
HIV INSTIs.
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