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The amide 64 (1000 g, 2.13 mmol) was further condensed to give the final
product 1 by dissolving first in EtOH (5 L), followed by addition of 32% aq. HCl
(500 mL) at RT to be converted to HCl salt. After filtration, the filtrate was heated at
75 °C for 4 h. The resulting suspension was cooled to 0 °C, then filtered to give the final
product 1 as a white solid (922 g, 89%). From starting material, the product was prepared
as a white crystal with 69% total yield without using expensive protecting groups, amide
coupling reagents or column chromatography. Only cheap and environmentally friendly
solvents such as toluene, THF, i-PrOH and EtOH were used. The robust and convenient
route provides a good solution for further scaling up of the drug molecule.
Chemistry and Pharmacology of Drug Discovery
12, 41
7. Summary
In summary, daridorexant, a new selective DORA agent, acts as a competitive orthosteric
antagonist for GPCRs OX1R and OX2R, exhibits good brain penetration, promotes sleep
with preserved sleep-architecture, and leaves no next-morning side effects. It is a better
substitution of traditional pharmacotherapies of hypnotic agents such as benzodiazepines.
To medicinal chemists’ interests, PK/PD study, metabolism, SAR study and synthesis of
the drug were all discussed. Other orexin drug candidates in the clinical trials, both
antagonists and agonists, have been briefly overviewed.
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Section IV. ANTI-INFLAMMATORY DRUGS
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________________________________________________________________________________
Deucravacitinib (Sotyktu): A First-in-Class
Deuterated TYK2 Inhibitor for the Treatment
of Plaque Psoriasis
Daljit Matharu
Deuteromethylamide supresses N-demethylation via deuterium kinetic
High selectivity for TYK2 over JAK1, JAK2, and JAK3
1. Background
In recent years, immune-mediated and autoimmune chronic inflammatory diseases have
emerged as a leading cause of morbidity, with conditions such as psoriasis, psoriatic
arthritis, axial and peripheral spondyloarthritis, as well as inflammatory bowel diseases
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.
FDA approved in 2022 for patients with plaque psoriasis
isotope effect
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Chemistry and Pharmacology of Drug Discovery
(IBDs) having an estimated prevalence of 5–7% in the Western world.1 Research into the
pathogenesis of immune-mediated inflammatory diseases has led to significant advances
in understanding human autoimmunity, which in turn has enabled improvements in
diagnosis and, most importantly, armed researchers with key information needed to
1
develop effective therapies.
Amongst the numerous autoimmune chronic inflammatory diseases, psoriasis is
a debilitating skin condition that causes a rash with itchy, scaly patches most commonly
occurring on the knees, elbows, trunk, and scalp, of which plaque psoriasis is the most
widespread. According to current studies, 125 million people worldwide (2–3% of the total
2
population) have psoriasis.
The disorder is caused by an over-reactive immune system that
causes skin cells to multiply up to ten times faster than normal, leading to the accumulation
of bumpy patches on the skin. Common triggers for psoriasis include emotional stress,
infection, skin injury, certain medications, such as beta-blockers, and changes in body
3
temperature due to the weather.
Widely used treatment options include corticosteroid creams such as
hydrocortisone, vitamin D3 ointment, retinoid creams, medication to slow skin cell
production (anthralin), and moisturizers for dry skin and coal tar. While these treatments
provide sub-optimal relief of symptoms, effective treatments that address the underlying
causes of inflammatory disease have remained elusive.
The Janus kinases (JAKs) are a family of intracellular tyrosine kinases (JAK1, 2,
3, and TYK2) that bind to distinct cell surface cytokine receptors, playing an essential
role in the signaling of numerous cytokines that have been implicated in the pathogenesis
of inflammation. As a result, small-molecule inhibitors of the JAK kinases have offered a
promising approach to treat a variety of serious inflammatory and autoimmune diseases.
4
The JAKs contain seven distinct homologous regions consisting of four
5
1).
structural domains (Figure
One of their characteristic features is the two structurally
related domains JH1 and JH2. JH1 is the active kinase catalytic domain, while JH2 is
referred to as the pseudokinase domain that closely resembles a catalytic domain but
possesses a series of individual residue and conformational differences that prevents it
from being catalytically active.
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Chapter 15. Deucravacitinib (Sotyktu)
Figure 1. Schematic representation of functional domains of the JAK family of kinases
To date, a number of small-molecule pan-JAK inhibitors or modestly selective
JAK inhibitors have been approved by regulatory agencies or are in different stages of
clinical development. These first- and second-generation inhibitors are active site-directed
inhibitors that bind to the ATP site of the catalytic domain (JH1 domain) of the JAK protein
(selected examples shown in Figure 2). Because of the high structural homology of the
ATP-pockets across the kinome and especially within the ATP binding site of the JAKs,
the development of highly selective JAK inhibitors has presented researchers with a
momentous challenge. As a result of cross-inhibition, dose-limiting side effects have been
documented, including risk of infection associated with over-immunosuppression, anemia
or leukopenia and neutropenia, and other rare yet serious adverse effects that have led the
to issue a “black box” warning for some JAK inhibitors.
FDA
6
Hence, the narrow
therapeutic index of current JAK inhibitors represents an unmet medical need to be
addressed to discover safer alternative treatments for cytokine-driven inflammatory
conditions.
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