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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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Chemistry and Pharmacology of Drug Discovery
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________________________________________________________________________________
Daridorexant (Quviviq): An Antagonist of
Orexin Receptors for Treating Insomnia
Dexi Ya ng
1. Background
As human beings, we spend one-third of our lives sleeping. Sleep plays a vital role in our
health and well-being throughout our lives. Inadequate sleep can hurt our body and mind,
affect our abilities to focus, and in a long term cause serious health problems such as
diabetes, metabolic disorder and depression.
falling asleep, frequent awakenings, short sleep duration, early waking up, etc.
estimated 10–20% of people suffer from sleeping disorder, but very few of them are
under therapy. Although insomnia is not fatal, it directly hurts quality of life, causes
daytime fatigue, inattention, bad mood, low energy levels, and increases risks of traffic
and work-related accidents.
Ironically, insomnia costs the US economy more than $100 billion per year, but
very few people get effect therapy. Although 70–80% of insomnia can be improved via
changing sleep habits, many people still need medicines.
pharmacotherapies have many limitations, and we will explain them in the following
4
1
Symptoms of insomnia include difficulty in
5, 6
2, 3
It is
Traditional
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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Chemistry and Pharmacology of Drug Discovery
paragraph. It is still an unmet medical need. But since insomnia affects so many people, it
is also a significant commercial opportunity for the pharmaceutical industry.
The pharmacotherapy of insomnia mainly includes four types of medications
approved by the FDA: the “Z” sedative hypnotics, benzodiazepines, melatonin receptor
7
agonists and the most recent orexin receptors antagonists.
The “Z-drugs,” such as zolpidem (2), eszopiclone (3) and zaleplon are allosteric
GABA-A subunit alpha-1 receptor modulators. They are generally selected as the firstline medications for insomnia, with each drug providing a different range of suppression
of CNS (central nervous system) activity as well as different onset and duration for
patients. The common side effects of Z-drugs are mainly the next-day hangover effect of
residual drowsiness, dizziness, and ataxia. The FDA has specifically warned that
zolpidem (2) and eszopiclone (3) can impair next-day operation of machinery and
8
driving.
The other class of drugs for insomnia are benzodiazepines. There are several
benzodiazepines on the market, such as lorazepam (4) and diazepam (5). They generally
have short half-life, and less next-day hangover effect in comparing with the Z-drugs.
However, they disrupt normal sleep patterns, reduce rapid eye movement (REM) sleep,
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Chapter 14. Daridorexant (Quviviq)
and consequently decrease coordination the next morning after administration.4 For these
reasons, they are still not ideal treatment for insomnia, especially for the older population.
Melatonin (6) is a hormone produced in the brain in response to darkness.
People believe melatonin can help with sleep for a long time, so it is sold as a dietary
supplement in drug stores. There are more than 30 million people using it to alleviate
insomnia. In fact, it is not even enlisted in clinical guidelines due to lack of efficacy and
9
safety studies.
Interestingly, based on this natural product, Takeda further optimized it
and discovered ramelteon (Rozerem, 7) approved for treating insomnia by the FDA in
10
2005.
It is an agonist of melatonin receptor in the suprachiasmatic nucleus (SCN), not
targeting the GABA-A receptors as Z-type of drugs we discussed earlier. However,
ramelteon was approximately 33% less effective at improving latency to persistent sleep
11
(LPS) in adults when compared with placebo.
So far, the pursuit of more effective
pharmacological treatment is still in progress. New medications must consider more
factors, especially sleeping patterns, drug safety, efficacy and no next-day hangover
effect.
In the last two decades, orexin receptors OX1R and OX2R attracted a lot of
attention. They are two G protein-coupled receptors (GPCRs) modulated by two
neuropeptides orexin A (33 amino acids) and orexin B (28 amino acids) generated in
hypothalamus (Figure
1). Two research groups, one is the Yanagisawa group at the
Howard Hughes Medical Institute in Dallas, and the other is the Sutcliffe group in The
Scripps Research Institute in La Jolla identified the two neuropeptides independently.
13, 14
Orexins were named after Greek word “orexis” because initially they were considered as
peptides relating to appetite. It was soon found that orexin signaling played a key role in
the sleep/wake circadian cycle based on several solid facts. One is the correlation that
narcolepsy or cataplexy in dogs was linked to a loss-of-function mutation in the OX
R
2
GPCR in dogs. The other is that low level of the orexin peptides was observed in the CSF
of narcolepsy patients. Low concentration of orexin A or orexin B in the brain causes low
energy level or sleep, while high concentration of the neuropeptides brings more energy
or less sleep. Based on these observations, as well as gene knocked off rat experiments, it
was hypothesized that small molecule orexin agonists could keep people awake to cure
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Chemistry and Pharmacology of Drug Discovery
patients with narcolepsy, while orexin antagonists could help people sleep. Guided by
this hypothesis, small molecule orexin antagonists were invented to cure patients with
insomnia.
Figure 1. Diagram of the generation of Orexin A and Orexin B from prepro-orexin and
their activation of OX1 and OX2 receptors. Subsequent signaling cascades involve
2+
phospholipase C (PLC), leading to elevated Ca
transmission. Source: Boss et al.
12
/with permission of John Wiley & Sons
concentration to enhance synaptic
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Chapter 14. Daridorexant (Quviviq)
In the past decade, several structurally diverse orexin receptor antagonists have
been clinically investigated. Of all the drug candidates, those inhibit both OX1R and
OX2R are called dual orexin agonists (DOAR), while those inhibit only one orexin are
called SORA. The FDA approved Merck’s suvorexant (8) as the first-in-class (FIC) in
Later in 2019, Eisai’s lemborexant (9) was approved.
2014.
compound daridorexant (1) from Idorsia was approved in 2022.
15, 16
Soon after, the third
17
They are all DOARs
and share many features. Other than these three approved drugs, there are several clinical
compounds either failed or still under development. One is almorexant (10), a DOAR, but
18
failed due to tolerability issues.
The other is seltorexant (11) which is still under
development by Minerva Neurosciences and Janssen Pharmaceuticals. Different from
other DOAR antagonists, it is a selective antagonist of the orexin OX2 receptor (2SORA), with 100-fold greater binding affinity for the OX2 receptor over the OX1
19
receptor.
patients or people suffering from low concentrations of orexin neuropeptides.
One limitation of all orexin receptor antagonist is that they exclude narcolepsy
20
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Chemistry and Pharmacology of Drug Discovery
It is worth noting that on the contrary to orexin antagonists, small molecule
orexin agonists have also been validated to show efficacy on narcolepsy patients. In this
arena, Taketa was the earliest runner and had two clinical compounds TAK-925 and
21, 22
TAK-944.
TAK-925 has been used to validate MOA via IV administration. Due to
high metabolism, it was stopped in Phase 1b. The other is an oral candidate TAK-944,
which was also stopped in Phase 2 due to hepatotoxicity. Now the only small molecule
23
orexin agonist in clinical trial is MK-6552.
Limited publication revealed that Merck’s
orexin agonists have more complicated cores and substituents. All examples in their
patents feature multiple congested chiral centers, and hopefully they can fix high
metabolism and hepatotoxicity issues observed in TAK candidates, while maintain good
brain penetration and low dose required by CNS drugs for everyday administration.
24, 25
2. Pharmacology
Daridorexant (1) is a highly potent small-molecule antagonist on both GPCR receptors
OX1R and OX2R. As a CNS drug to promote sleep, it is a good brain penetrating
antagonist with fast onset, and a duration of action just long enough to cover nighttime
sleep, while avoiding residual morning effects.
mechanism, that is to selectively inhibit only OX1R and OX2R to allow sleep to occur,
bypassing other receptors such as GABA-A, thereby to avoid adverse effects associated
with inhibitors of those receptors. Different from previous medications, daridorexant (1)
promotes sleep without altering the sleep architecture.
shortens non-REM sleep in physiological proportions.
patients or people suffering from low concentrations of orexin neuropeptides, should
avoid taking daridorexant (1) due to its MOA of deactivating orexin receptors which
20
aggravates narcolepsy.
26
It promotes sleeping via a new
12, 27
It increases REM sleep but
28
As a precaution, narcolepsy
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Chapter 14. Daridorexant (Quviviq)
3. Structure–Activity Relationship (SAR)
The structure of daridorexant (1) features a proline core, an aryl amide and a
benzimidazole pendant attached at α-position. The proline hit was identified at Actelion
via high-throughput screening using Ca
receptor antagonists. The proline sulfonamide (12) in Figure 2 has a low molecular
weight of 461.42 and shows significant activity in the calcium release assay. It also
showed good properties necessary for CNS drugs, especially good brain penetration, no
liabilities of being P-glycoprotein (Pgp) substrate, low in vitro human liver microsomal
metabolic stability and no obvious cytochrome inhibitory activity.
2+
release assays in the search for dual orexin
12, 29
Figure 2. Structure and properties of OX1/OX2 HTS hit
Starting from hit 12, earlier optimization mainly focused on these three aspects
to improve both potency, brain penetration and general ADME properties: (1)
replacement of the bromothiophene with more drug-like aryl or alkyl groups; (2)
optimization of the sulfonamide moiety with better bioisostere; (3) screening of better
heterocycles other than aniline which may have hERG liability, as well as identifying
more robust groups other than alkyl sulfide that could be easily oxidized.
29
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Figure 3. Influence of proline core chirality
Lead optimization was conducted by (1) screening aryl groups on sulfonamide
and (2) replacing aniline on amide. It has been observed that derivatives from this
practice generally maintained potencies toward OX1 and OX2, but inhibition toward
CYP3A4 varied a lot. After thoroughly screening the two vectors, 13 (Figure 3) was
discovered with high potencies on both OX1 and OX2, while with the least liability
toward CYP3A4 (15 μ M). When 13 was further profiled in an in vivo blood-brain barrier
penetration experiment in male Wistar rats, it showed excellent brain penetration with
brain concentration of [B] = 1219 ng/g comparing to plasma concentration of
[P] = 2667 ng/mL, and [B]/[P] ratio is 46%. Its enantiomer 14 has also been prepared and
the chirality has been confirmed to be important to potency. Different to the potent S
enantiomer 13, the R enantiomer 14 tested to have no antagonist activity for either orexin
receptor.
Chemistry and Pharmacology of Drug Discovery
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Figure 4. Selected OX1R/OX2R agonists via scaffold hopping
Chapter 14. Daridorexant (Quviviq)
In addition to changing both aryl groups, scaffold hopping has also been
conducted and some examples were collected in Figure
scaffold optimization. A simple addition of 3-methylene gave compound 15, which
retained some potency, but inferior to the parent compound 12. Further investigation of
this type of compounds showed very low brain concentration. Another strategy was to
replace pyrrolidine with piperidine to give compound 16. Unfortunately, although only
added one carbon, 16 substantially lost potency. Interestingly, analog 17 with a bridged
bicyclic template containing both piperidine and pyrrolidine regained potency. Further
exploration into bicyclic templates showed the bicyclic [3.3.0] as in 18 and [3.1.0] ring as
in 19 did not have advantages over the simple prolidine core, but added a lot of synthetic
complexities for the scaffold synthesis.
After all these seminal studies, 13 was chosen as a tool compound. It was then
fully profiled. In addition to exhibiting good potency on both GPCR receptors, it was also
proved to be a non Pgp substrate (efflux ratio = 1.1) based on a human multidrug resistant
protein transporter assay (MDR-1). It also showed human plasma protein binding (hPPB)
as well as rat plasma protein binding (rPPB) of 99.3%, and metabolic stability in human
liver microsomes (HLM) of 140 μL/min//mg. Further more, the compound showed no
significant cytochrome P450 inhibition. Unfortunately, its PK data showed short half
lives of only 1.9 h in rat and 1.7 h in dog respectively. In general, although 13 showed
4. SAR is very narrow in the
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