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hydrolysis of 25 under the condition of NaOH/n-heptane will afford the desired ciprofol
(1) in 90% yield with over 99% de. The overall yield of this endgame route was 12–14%.
Chemistry and Pharmacology of Drug Discovery
7. Summary
Dating back to the discovery of propofol (2) in 1977, the patent of propofol (2) has expired
for many years. When considering something in retrospect as medicine chemists, we must
think about why ciprofol (1) is still discovered and developed? Firstly, drug is developed
to meet the clinical needs of patients as the highest priority. Secondly, patentability is a
magic weapon for drugs. Ciprofol (1) is currently approved to indications including
sedation in gastrointestinal endoscopy, followed by anesthesia during the
surgical/procedure of nontracheal intubation, induction and maintenance of general
anesthesia, and sedation during intensive care by China in 2020. Numerous clinical trials
investigating ciprofol (1) have consistently demonstrated its benefits,
tolerance, higher sedation satisfaction score, and reduced occurrence of adverse reactions
(respiratory depression and decrease blood pressure). Particularly noteworthy is its
remarkable effectiveness in significantly decreasing the frequency of injection-related pain.
There is a scarcity of long-term medication experience and comprehensive clinical data
validating its efficacy in broader clinical scenarios due to a short period on the market. Still,
a lack of clinical research data about ciprofol (1) in patients under 18 years old and pregnant
and lactating women will not be recommended for their treatments. The familiarity and
proficiency of anesthesiologists with propofol (2) make it challenging to envision a fullscale transition to ciprofol (1), as well as medicinal cost for patients. Compared to propofol
(2), the complexity of chemical process is still more challenging due to a chiral center of
one side chain. With further investigation and understanding, ciprofol (1) holds the
potential to offer additional benefits to patients, ultimately enhancing the field of anesthesia.
2
including enhanced
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13
________________________________________________________________________
Rimegepant (Nurtec ODT): A CGRP
Receptor Antagonist as a Treatment of
Episodic Migraine
Yuqi Lavender Zha and
Guanglin Luo
FDA’s 2020 approval rimegepant (Nurtec ODT, 1), a calcitonin gene-related peptide
(CGRP) receptor antagonist as a treatment of episodic migraine in adults, is good news
for millions of patients suffering from episodic migraine.
Rimegepant (1) is the second CGRP small-molecule antagonist on the market.
The other two small-molecule CGRP receptor antagonists, ubrogepant (Ubrelvy, 2) and
atogepant (Qulipta, 3) were approved in 2019 and 2021, respectively.
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
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Chemistry and Pharmacology of Drug Discovery
1. Background
Migraine headache is commonly characterized by recurrent headaches lasting 4–72 h
with moderate to severe, pulsating pain. Associated symptoms may include nausea and/or
vomiting, and increased sensitivity to light and sound (photophobia and phonophobia,
respectively).
Although it is not a life-threatening disease, due to the severity of the headache, its long
duration, and high prevalence, migraine is a very disabling disorder, which has long
become a significant public health issue in both sexes and all age groups, especially
young and middle-aged women. According to the Global Burden of Disease Study, from
1990 to 2019 (the latest one), migraine remained second
disability (both sexes, all ages) for 30 years, but topped the list in young women in the
global burden disease of 2019.
disability (YLDs) globally, accounting for 4.76% of all YLDs caused by 396
with
diseases.
availability of migraine-specific drugs, nonsteroidal anti-inflammatory drugs (NSAIDs)
such as, aspirin, acetaminophen, ibuprofen, and naproxen were used to treat mild
migraine pain, but do not work in the majority of migraine patients.
efforts accumulated in this area, the pathophysiology of migraine started to reveal itself,
but contention remains, especially around the initiation of migraine. There are two
dominant hypotheses about the mechanism behind migraine: the vascularly focused
hypothesis and the neuroanatomically focused hypothesis (Figure
2
The influence of migraine is often underestimated by non-migraineurs.
among the world’s causes of
3
Migraine was responsible for 41.1 million years lived
4
In the past, without understanding of the mechanism behind migraine and
1
Since research
1).
Figure 1. Overview of migraine-specific medications and their possible
targets. Source: de Vries et al.
The vascularly focused hypothesis centered around the perivascular CGRPergic
transmission of the trigemino-vascular system, which proposed a three-step model of
migraine initiation: (1) release of several neuropeptides including CGRP from the
5
/with permission of Elsevier
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Chapter 1 . Rimegepant (Nurtec ODT)
3
perivascular trigeminal nerve branches; (2) induction of vasodilation by CGRP; (3)
Activation of nociceptors on the trigeminal nerve by vasodilation, which is eventually
followed by pain perception.6 This hypothesis supports the use of 5-HT
namely triptans for acute treatment of migraine. It is believed that 5-HT
1B/1D
agonists,
1B/1D
triptans elicit
their antimigraine action by vasoconstriction of excessively dilated intracranial,
extracerebral arteries and/or inhibiting the release of inflammatory neuropeptides from
7
perivascular trigeminal sensory neurons.
8
However, because 5HT receptors are universally expressed in many organs and
drugs.
Triptans 4–10 are now all available as generic
tissues, one of the major concerns with triptans is their potential adverse effect on the
cardiovascular system, which led to restricted use of triptans in patients with
cardiovascular diseases. It has been suggested that 5-HT
vasoconstriction, while inhibition of neuropeptide release is mediated via the 5-HT
receptor activation results in
1B
1D
receptor. However, a randomized clinical trial of the 5-HT1D selective agonist PNU-
9
142633 failed to demonstrate significant efficacy over placebo.
5-HT1F receptor has
become the next target, which is also believed to inhibit pre-junctional release of CGRP
in the trigeminal ganglion and does not play a role in vasoconstriction. One brainpenetrant 5-HT1F receptor agonist, Lasmiditan has been approved by the FDA for the
5
acute treatment of migraine with improved cardiovascular safety.
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