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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5613_Библиотеки_им_академика_М_И_Перельмана
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Just like all other NNRTIs, doravirine (1) binds to the allosteric NNIBP, which
is approximately 10 Å away from the DNA polymerase active site (Figure
first-generation NNRTIs 2–5, doravirine (1), the binding to HIV-1 reverse transcriptase is
less dependent on K103 and Y181. Instead, the most relevant doravirine (1)-reverse
transcriptase interaction is the hydrophobic interaction between its phenyl ring and the
side chain of V106.
Doravirine (1) is featured with excellent antiviral activity, favorable safety and
tolerability profiles, low potential for drug resistance, and drug–drug interactions (DDIs).
As a new pyridone NNRTI, doravirine (1) exhibits an excellent efficacy in suppressing
HIV-1 viral replication (EC
can effectively inhibit many HIV-1 strains with NNRTI-resistant mutations including
K103N, Y181C, and G190A as depicted in Table
(11), etravirine (12) and rilpivirine (7), doravirine (1) is potent against the wild-type
enzyme as well as the clinically relevant single-point and double-point mutants.
Drug WT
Efavirenz (11) 39 1400 90 3200
Etravirine (12) 33 44 240 590
Rilpivirine (7) 36 44 120 370
Doravirine (1) 19 42 25 54
Chemistry and Pharmacology of Drug Discovery
16
= 20 nM). Regarding its resistance profile, doravirine (1)
50
2. Unlike its predecessors efavirenz
Table 2. Mutant Profile NNRTIs
(IC
nM)
95
K103N
nM)
(IC
95
Y181C
(IC
95
nM)
5). Unlike
17
K103N/Y181C
nM)
(IC
95
Source: Côte et al. 17/with permission of Elsevier
Doravirine (1)-resistance is usually associated with the combination of
V106A/G190A/F227L, suggesting the limitation of doravirine (1) against certain HIV-1
drug-resistant strains.
3. Structure–Activity Relationship (SAR)
Using a cell-based assay, Merck’s initial hit from high-through screen (HTS) provided
tetrazole thioacetanilide 15 as one of the two interesting hits. It was a potent inhibitor of
HIV-1 reverse transcriptase polymerase (pol), with sub-micromolar activity in a cell
assay and significant in vitro activity on the K103N mutant strain. Extensive optimization
resulted in tetrazole thioacetanilide 16, which had a reasonable oral bioavailability but
suffered from a short half-life of merely 0.23 h in rat.
18
19
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Chapter 2. Doravirine (Pifeltro)
Inspired by Glaxo Wellcome’s acetanilide para-sulfonamide, GW-8248 (17),
Merck decided to use it as their starting point. Replacing the benzophenone moiety in 17
conveniently provided novel chemotype diarylether 18 although it was only moderately
potent for the wild-type HIV reverse transcriptase as well as clinically relevant mutants
K103N and Y181C. Further structure-activity relationship (SAR) investigation revealed
that the chloro- and nitrile-substituents on 17 were crucial to its potency, probably by
making all three phenyl rings A, B, and C more electron-deficient. Decorating diarylether
18 with additional chloro- and nitrile-substituents on its A- and B-ring, respectively,
resulted in highly potent halogenated analog MK-4965 (19) where the phenylsulfonamide
was replaced by an aminoindazole. It possessed high levels of potency against wild-type
and key mutant viruses, excellent oral bioavailability and overall pharmacokinetics and a
20, 21
clean ancillary profile. It was nominated as a development candidate.
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Chemistry and Pharmacology of Drug Discovery
Meanwhile, replacing the phenyl B ring with a novel pyridone core structure led
to the discovery of pyridone 20 with increased polarity and binding affinity. It had better
22
antiviral activity against HIV-1 strains with the K103N/Y181C mutation.
Systemic SAR optimization of the methyl substituent revealed that the
trifluoromethyl-pyridone derivative 21 was potent for both wild-type reverse
transcriptase and double mutant (K103N/Y183C) enzyme inhibition. Even though 21
showed improved plasma stability, it suffered poor solubility and low oral absorption due
to an esoteric, highly ordered intermolecular hydrogen bonding of the pyrazolopyridine
motif. Eventually, optimization led to the replacement of pyrazolopyridine with methyltriazolone to provide doravirine (1). Even though doravirine (1) was not as potent as MK4965 (19), it had a superior DMPK profile. It became the clinical drug candidate and
10, 16, 17
eventually achieved the FDA approval in 2018.
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Instead of a thorough tabulation of the voluminous SAR in literature, only two
important optimization processes are summarized here so we can learn important lessons
of drug design and medicinal chemistry.
Table 3. SAR for the Optimization of the 4-Position of the Pyridone Core
Chapter 2. Doravirine (Pifeltro)
23
— — Inhibition of
RT
Compound X (IC50 nM), WT WT K103N/Y181C t
Efavirenz (11)
—
20
21
—
—
—
—
Me 7 12 96 0.8
Cl 3 8 69 2.2
CF3 3 17 69 7.0
Br 2 4 21 1.7
SMe 9 15 33 1.5
c-Pr 7 12 110 1.5
2 39 3200 –
Spread
IC
95
(50% NHS;
nM)
Source: Adapted from Burch et al. 23
First, let us look at the impact of the 4-position of the pyridone core on potency.
As shown in Table
3, the 4-methyl pyridone derivative was tested to be a potent inhibitor
1/2
rat)
–
(h,
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of both wild type and mutant forms of HIV reverse transcriptase using the SPREAD
assay in 50% normal human serum (NHS). Similarly, 4-chloropyridone 20 and 4trifluoromethylpyridone 21 were just as potent, as were the bromo-, methylsulfanyl-, and
cyclopropyl-pyridone analogs. 4-Trifluoromethylpyridone 21 stood out because it had the
longest half-life in rat, suggesting potentially a higher bioavailability. As a result, 4trifluoromethyl substituent was adopted as optimal.
Next, let us examine the impact of the sidechain substituents on the potency and
solubility of 4-trifluoromethyl pyridones.
Table 4. Structure-activity and solubility relationship for side chain replacements
Chemistry and Pharmacology of Drug Discovery
17, 23
Het Inhibition of
RT
Spread IC95, WT
(50% NHS; nM)
Solubility
(μM)
(IC50 nM), WT
3 17 1.1
(21)
6 53 5.2
6 210 3.1
390 – 23
16 100 44
43 150 28
(1)
Because 21’s unfortunate propensity to form highly ordered intermolecular
hydrogen-bonding that resulted in poor solubility, the pyrazolopyridine sidechain was
systematically optimized. As shown in Table
11 19 45
4, replacement sidechains were chosen to
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remove at least one hydrogen bond donor or acceptor to minimize the key donor–
acceptor hydrogen bond with the backbone of K103. Replacing the pyrazolopyridine on
21 with indazole led to improvement of kinetic solubility in aqueous media despite being
more lipophilic, presumably due to removal of the pyridine nitrogen of the donor–
acceptor hydrogen bond pair. The most significant improvement of solubility came when
a monocyclic thiazole was employed to replace the bicyclic heterocyclic sidechains.
Although the thiazole analog lost much of its potency, installation of an additional methyl
group on thiazole restored the potency. Gratifyingly, isosteric methyltrizolinone (1)
afforded drastically improved solubility without loss of cellular potency relative to
pyrazolopyridine on 21.
Chapter 2. Doravirine (Pifeltro)
17, 23
4. Pharmacokinetics and Drug Metabolism
After oral administration, doravirine (1) is quickly absorbed due to its high-absolute
bioavailability (64%). In healthy volunteers, the maximum plasma concentration (C
reached in 1.5 h (range: 1–5 h) after a single dose of doravirine (1). The plasma half-life
) of doravirine (1) is approximately 12–21 h and its clearance is approximately
(t
1/2
3.73 L/h. The hepatic biotransformation of doravirine (1) is processed by cytochrome
P450 (CYP450)-3A4 and P-glycoprotein (P-gp), while other compounds that induce or
inhibit CYP3A may alter the plasma concentration of doravirine (1), thereby affecting its
10
5).
efficacy (Table
max
) is
Table 5. Pharmacokinetics of NNRTIs
Generic Approval year
Efavirenz (11) 1998 600 qd 40–55 CYP3A4
Rilpivirine (7) 2011 25 qd 50 CYP3A4
Doravirine (1) 2018 100 qd 11–15 CYP3A
Ainuovirine (14) 2021 150 qd 26 CYP2C19
Dose
(mg)
T
(h)
1/2
Metabolic
enzyme
Source: Adapted from Namasivayam et al. 10
Doravirine (1) is rather pervious to drug metabolism, 75% of the 14C-labeled
drug was found in plasma unchanged. The most abundant metabolite M9 (22), is a
product of oxidative metabolism that added an additional oxygen. The published structure
of M9 (22), if correct, was probably a result of several steps of complicated
rearrangements after metabolic hydroxylation. A glucuronide of an oxidative metabolite
(M7, 23) and an N-acetyl-cysteine conjugate of doravirine (M15, 24) contributed a
cumulative 2.8% of the radioactivity in this matrix. Other metabolites were less
significant.
24
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Chemistry and Pharmacology of Drug Discovery
Doravirine (1) is a P-gp substrate but P-gp efflux is not expected to play a
significant role in limiting doravirine (1) absorption or to be involved in the elimination
of doravirine (1). The disposition of doravirine (1) in human is shown below. The
primary route of elimination is excretion through feces (90%) with the remaining
18, 24
elimination through urine (10%).
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Chapter 2. Doravirine (Pifeltro)
5. Efficacy and Safety
Because of the rapid development of resistance, NNRTIs cannot be applied as
monotherapy in the management of HIV. The oral use of doravirine (1) 100 mg should be
combined with other antiretroviral drugs for the treatment of HIV-1 infections in
treatment-naïve adults.
In a Phase III non-inferiority trial of treatment-naive adults, 84% patients on the
combination drug DOR/3TC/TDF with 100 mg doravirine (1) once daily co-formulated
with 3TC (3) and TDF (5) achieved plasma HIV-1 RNA < 50 copies/mL at week 48. In
comparison, a similar three-drug combination for
achieve the same goal. DOR/3TC/TDF was generally well tolerated with significantly
fewer neuropsychiatric adverse events observed with doravirine (1) than with
(11)
and a lipid profile superior to efavirenz (11) as assessed by change from baseline in
LDL-C and non-HDL-C.
Doravirine (1) has an IC
total maximum serum concentration (C
25
of 88 μM against hERG, which is 30× higher than the
50
) and 126× higher than the unbound C
max
steady-state concentrations of doravirine (1) at 100 mg once daily, the approved clinical
dose. In clinics, a supratherapeutic dose of 1200 mg did not induce clinically meaningful
differences in QTc and no issues related to delayed ventricular repolarization have been
26
reported.
EFV/3TC/TDF had 81% patients
efavirenz
max
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Chemistry and Pharmacology of Drug Discovery
6. Synthesis
Merck Process Chemistry carried out extensive optimizations to make doravirine (1).
Herein, we only focus on the supply route and the final manufacturing route.
Generally speaking, discovery chemistry routes to make active pharmaceutical
ingredients (APIs) are not amenable to process chemistry routes. This does not come as a
surprise because discovery and process chemistry have different roles. Discovery
chemistry enables making as many analogues as possible so the synthetic routes are often
modular. A common intermediate can afford many derivatives to provide glimpse of
SAR. In contrast, which drug to make is already known for process chemistry. Therefore,
process routes are often convergent to make the APIs quickly, cheaply, and safely on
large scales.
Merck’s supply route commenced with an iridium-catalyzed meta-borylation of
(25), which was superior to the palladium-catalyzed protocol that was associated with
dichlorination.
(bpy) in cyclohexane (CyH) worked just as well as the expensive 4,4′-di-tert-butyl-2,2′-
bipyridyl (dtbpy). After switching the solvent to acetone, oxidation of the resulting
pinacol boronate intermediate was carried out in one-pot to give phenol 26. Phenol 26
was then coupled with 2-chloro-3-fluoro-4-(trifluoromethyl)pyridine (27) to assemble
diarylether 28 via a selective (for the meta-fluorine over the ortho-chlorine) S
reaction. Hydrolysis of the α-chloropyridine moiety on 28 using NaOH led to pyridone
29, which was converted to nitrile 30 using a simple S
crucial S
straightforward to afford adduct 32. Triazolinone chloride (31) was chosen over its
methylated derivative due to its ready availability as it is a shared intermediate for
making another Merck drug aprepitant (Emend), a substance P/neurokinin 1 receptor
antagonist prescribed to treat nausea and vomiting caused by chemotherapy or surgery.
Finally, selective methylation of 32 then delivered
screening a variety of bases and solvents.
As important, it was discovered that inexpensive ligand 2,2′-bipyridyl
Ar cyanation with CuCN. The
N
2 coupling between pyridone 29 and triazolinone chloride 31 was
N
doravirine (1) optimally after carefully
27
N
Ar
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Chapter 2. Doravirine (Pifeltro)
Merck’s manufacturing route for making doravirine (1) was truly innovative.
Instead of using substituted pyridines as their starting materials, they decided to build the
pyridone core structure via cyclization. After extensive experimentations, flow chemistry
was employed to prepare aryloxyl-pyridone 30. As shown below, Aldol condensation
between ester 33 and vinylogous ester 34 mediated by potassium tert-amyloxide in
toluene was carried out in a flow reactor with aid of triethylamine. The unquenched aldol
exit stream from the flow reactor was collected in a cooled receiver vessel to which
trifluoroacetic anhydride was added synchronously to provide diene 35. Amination,
cyclization, and dehydration took place when diene 35 was treated with 28 equiv of
ammonia at 60 °C to produce aryloxyl-pyridone 30 in 68% yield.
27
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