Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5613_Библиотеки_им_академика_М_И_Перельмана
.pdf
228
https://t.me/med1917
Chemistry and Pharmacology of Drug Discovery
times as potent as CC112273.58 CC112273 and CC1084037 were bound 98.2%, 99.8%
and 99.3% to human plasma protein respectively. The times to reach steady state for
ozanimod (1) and CC112273 in healthy individuals are 102 h and 45 days and the time to
reach maximum plasma concentration T
is 6–8 h for Ozanimod and 10 h for
max
CC112273. Food intake regardless of high or low fat and caloric content in healthy
121
individuals did not affect the exposure of ozanimod (1) or its active metabolites.
Ozanimod (1) metabolism is complex and a metabolic pathway in human was
58
only recently proposed.
58
MAO-B.
Ozanimod (1) is eliminated through the urinary tract and has a mean single
Two of the key enzymes involved are cytochrome CYP3A4 and
oral dose excretion of 0.03% and 0.06%, a seven-day regimen mean excretion of 0.04%
to 0.09%, and a 28-day regimen mean excretion of 0.03% to 0.06%. Ozanimod was
shown to have a single dose renal clearance range from 0.116 to 0.287 L/h, seven-day
dosing regimen renal clearance range from 0.189 to 0.435 L/h and a 28-day regimen renal
122
clearance range from 0.229 to 0.291 L/h.
4. Structure–Activity Relationship (SAR)
S1PR1 consists of an extracellular N terminus with an alpha-helix structure that folds
over the top of the receptor, preventing ligand accessibility to the inner binding pocket.
123
In total S1PR1 includes seven transmembrane domains, hydrophilic extracellular and
63
intracellular loops. S1PR1 modulators were classified into class I and II agents.
Class I
modulators possess a polar head group with/without an acyl chain. Examples include
ML056, SEW2871, and ASP4058 (Table 1). The polar head group of ML056 is
composed of a phosphonate group and a primary amine, protonated at the physiological
conditions, while its tail consists of a phenyl ring with a meta-substitution of an alkyl
124
chain.
The phosphonate and protonated amine enable ML056 to effectively interact
with charged residues such as Tyr29, Lys34, Asn101, Arg120, and Glu121 at the binding
pocket of S1PR1 (Figure
124
5).
The phenyl acyl tail of ML056 fills the hydrophobic part
of the S1PR1 binding site, establishing selective hydrophobic interactions with the
124
aromatic and short aliphatic residues.
ML056 is an antagonist of S1PR1. However,
change in its structure such as lengthening its acyl tail and moving phenyl substituent to a
124
para position result in the conversion of antagonism to full agonism.
Fingolimod
phosphate, AFD(R), and amiselimod phosphate are also examples where lengthening the
alkyl chain and positioning of phenyl substituents led to the conversion of antagonism to
71,125
full agonistic activities on S1PR1.
Although class I S1PR1 modulators always need a
polar head group for interaction with the receptor, the presence of an acyl tail is not
45,126
necessary for effective binding such as SEW2871 and ASP4058.
A trifluoromethyl
moiety on phenyl ring provides the polar head group for SEW2871. In ASP4058, the
trifluoromethyl and a trifluoropropan-2-oxy group act as the polar head and establish the
126,127
ion–dipole interactions with Arg120 and Glu121 in S1PR1.
Though SEW2871 and
229
https://t.me/med1917
Chapter 11. Ozanimod (Zeposia)
ASP4048 are devoid of acyl tails, they possess bulky aromatic rings which enable the
interactions with aromatic residues at the S1PR1 binding pocket.
Table 1. S1PR1 modulators, chemical structures, pEC50 values, indication and clinical
trial phases
S1PR1 modulators Chemical structure pEC50 Indication/clinical trial
ML056
Fingolimod
6.1 RRMS/approved
Rett syndrome/I, II
Chemotherapy-induced
peripheral neuropathy/I
cognition, brain volume
loss/IV
Stroke inflammation/II
Amyotrophic lateral
sclerosis/II
Schizophrenia/II
Chronic inflammatory
demyelinating
Polyradiculoneuropathy/I
I
AFD (R) 8.4–8.8
Amiselimod
SEW2871
ASP4058
Ozanimod (1)
CYM-5442
10.1–
10.9
RRMS/II
CD/II
UC/II
Plaque psoriasis/II
5.5–7.7
8.1 RRMS/preclinical
Intracranial
aneurysm/preclinical
9.4–9.8 RRMS/approved
Liver disease/I digestive
system disease/III
CD/approved
UC
8.9 Chronic graft-vs-host
230
https://t.me/med1917
Chemistry and Pharmacology of Drug Discovery
disease/preclinical
RP-001
Siponimod 9.4–
Etrasimod 8.2–9.2 UC/III
Ponesimod
Cenerimod
11.1 RRMS/discontinued
SPMS/approved
10.1
8 RRMS/approved
9 Systemic lupus
Active dermatomyositis/II
Polymyositis/II
eosinophilic
esophagitis/II
Alopecia areata/II
CD/II, III
atopic dermatitis/II
Primary biliary
cholangitis/II
Chronic graft-vs-host
disease/II
Plaque psoriasis/II
erythematosus/II
Compound 26
(PMID:16190743)
Compound 43
(PMID:26751273)
GSK2018682
SAR247799 6.3–7.9 Microvascular coronary
BMS986104
Derivative 12
RP-101075
9.2 Preclinical
8.8
7.7 RRMS/discontinued
artery disease/I
8.7 Rheumatoid arthritis/I
9.6 Microvascular
thrombosis/preclinical
231
https://t.me/med1917
Chapter 11. Ozanimod (Zeposia)
BMS986104
Derivative 24
8.7 Autoimmune
disease/preclinical
Source: Kandjani et al. 63/with permission of Elsevier
Figure 5. S1PR1 in complex with ML056. Source: Adapted from Hanson et al.
S1PR1 consists of an extracellular N terminus with an alpha-helix structure that folds
124
over the top of the ligand-binding pocket,
hydrophilic extracellular and intracellular loops.
seven transmembrane domains, and
44
(b) ML056 consists of a head group
with a polar phosphonate and primary amine and a phenyl acyl tail which reflects the
highly amphipathic nature of the S1PR1 binding pocket. The residues involved in the
63
ligand binding have been highlighted. Source: Kandjani et al.
/with permission of
Elsevier
124
. (a)
Class II S1PR1 modulators do not require a polar head group to interact with the
receptor. Instead of an acyl tail, the presence of a phenyl ring enables them to establish
specific aromatic interactions with Phe210, Phe265, and Trp269.
molecule S1PR1 agonist that does not require interactions with either Arg120 or Glu121
yet is fully active in vivo to induce lymphopenia.
diethoxyphenyl moiety of CYM-5442 with the S1PR1 aromatic residues, Phe210, Phe265
and Trp269 is necessary for ligand binding and activity, while the aromaticity of the
binding site is not necessary for binding of S1P to the receptor.
group of CYM-5442 also induces further selectivity as this moiety has steric interactions
with Phe263 of S1PR3, but not with its equivalent resident Leu276 in S1PR1.
Most second generation S1PR1 modulators including RP-001, siponimod,
etrasimod, ozanimod (1), ponesimod, cenerimod, and GSK-2018682 are class II S1PR1
modulators.
10,128–133
63
CYM-5442 is a small-
45
The aromatic interaction between
63
The diethoxyphenyl
45
Cryo-electron microscopy structure of siponimod in complex with
232
https://t.me/med1917
Chemistry and Pharmacology of Drug Discovery
S1PR1 showed that in addition to Phe263, Siponimod also has steric clashes with I284 in
S1PR3 binding pocket which further explains its high S1PR1 over S1PR3 selectivity.
123
One of the common feature of class II modulators is the disubstituted phenyl ring with a
63
bulky substituent at the para position.
to meta position reduces the activities.
The relocation of the bulky substituent from para
63
Using cryo-EM data, structures of S1PR1 bound to siponimod, cenerimod,
123
ozanimod (1), and SEW 2871 were reconstructed by Yuan et al.
The polar headgroups
from the three agonists siponimod, cenerimod, and ozanimod (1) form direct contacts
with K34
N-ter
from the N-terminal capping helix.
123
In addition, upon aligning four
agonists in the S1PR1 structures, scientists found that the hydrophobic portion of the
ligands was located in a nearly identical narrow hydrophobic pocket of S1PR1. A subpocket of the orthosteric site was also identified to accommodate the subgroups of
agonists, such as the trifluoromethyl moiety of siponimod and SEW2871, the methoxy
moiety of cenerimod and the cyano moiety of ozanimod (1). These moieties form
hydrophobic interactions with the surrounding residues C206
L272
6.51
, and F273
6.52
from TM5 and TM6. When alanine replacement was generated in
5.43
, T207
5.44
, F210
5.47
the sub-pocket, the results of the signaling assay indicated that the activation potency of
all receptor variants decreased when sensing different agonists.
SAR247799, BMS986104 and compounds 12 and 24 are new S1PR1
134,135
modulators called S1PR3-sparing biased agonists.
SAR247799 activates S1PR1 on
endothelium without imposing receptor desensitization effect leading to the activation of
protection pathways in human endothelial cells with no lymphopenia.
63
This compound
possesses a polar head group of hydroxyacetic acid to interact with S1PR1 polar residues
at the binding site and the chlorophenoxy moiety at the other end to establish aromatic
63
interactions with the S1PR1 binding site residues.
alkyl tail attached to a tetrahydronaphthalene and a polar head group.
BMS-986104 derivatives possess an
63
,
5. Safety and Efficacy
The safety of ozanimod (1) in humans was first evaluated in a phase I, randomized
double-blind, placebo-controlled trial. The study found that ozanimod (1) was well
tolerated up to 3 mg as a single dose. Treatment emergent adverse events (TEAEs) were
mild to moderate and there were no severe TEAEs or dose-limiting toxicities. No
cardiovascular or pulmonary events were considered of clinical concern, and there were
no hepatic or ophthalmologic effects identified.
heart rate reduction which leads to the dose-escalation protocol in all subsequent clinical
122
trials.
therapeutic and supratherapeutic doses and did not raise any new safety concerns.
This study also determined that ozanimod (1) did not prolong the QTc interval at
100
Patients showed a dose-dependent
108,122
233
https://t.me/med1917
Chapter 11. Ozanimod (Zeposia)
5.1. Ozanimod to Treat Multiple Sclerosis
The phase II trial RADIANCE was a 24-week, double blind, placebo-controlled clinical
trial in RRMS patients, with the primary endpoint of the cumulative number of total
gadolinium-enhancing MRI lesions at weeks 12–24. The mean cumulative number of
gadolinium-enhancing lesions at weeks 12–24 was 11.1 (SD 29.9) with placebo
compared with 1.5 (3.7) with ozanimod hydrochloride 0.5 mg and 1.5 (3.4) with
ozanimod hydrochloride 1 mg.
nasopharyngitis and headache being the most common TEAEs. The maximum reduction
in mean heart rate by Holter monitoring during the first 6 h in ozanimod-treated
participants were less than 2 beats per min (bpm) compared with baseline, with no patient
having a minimum hourly heart rate less than 45 bpm. Electrocardiograms and 24-h
Holter monitoring showed no increased incidence of atrioventricular block or sinus pause
with ozanimod (1).
136,137
patients continued the treatment, and the placebo group were randomly switched to
ozanimod hydrochloride 0.5 or 1 mg/d. The efficacy results were confirmed with a low
number of new T2 lesions and GdE lesions on brain scans in all groups on ozanimod (1)
during the study period.
138
RADIANCE B phase III trial was a multicenter, randomized, double-blinded
doubly-dummy, parallel group, active-controlled study with relapsing MS at 147 medical
centers and clinical practices in 21 countries.
daily ozanimod 0.46 mg (equivalent to ozanimod hydrochloride 0.5 mg), 0.92 mg
(equivalent to ozanimod hydrochloride 1.0 mg) or once weekly intramuscular IFN β-1a
30 μg for 24 months. The primary endpoint was the annualized relapse rate (ARR) in
comparison to IFN β-1a 30 μg at 24 months. Adjusted ARRs were 0.17 with Ozanimod
hydrochloride 1.0 mg, 0.22 with Ozanimod hydrochloride 0.5 mg, and 0.28 with IFN β1a, with rate ratios vs IFN β-1a 0.62 for ozanimod hydrochloride 1.0 mg and 0.79 for
ozanimod hydrochloride 0.5 mg.
has greater efficacy than Ozanimod 0.46 mg and both doses were at least as effective as
102,122
IFN β-1a.
RADIANCE B study showed treatment with ozanimod (1) resulted in less brain
volume loss, which suggested that ozanimod might protect against structural changes
associated with disease progression. During dose escalation, no clinically meaningful
cardiac findings were reported including second-degree or third-degree atrioventricular
block or symptomatic bradycardia.
greater efficacy on clinically meaningful measures of disease activity (relapses and MRI
lesions) than treatment with IFN β-1a.
A similar 12-month, multicenter, double-blind, phase III trial SUNBEAM was
conducted between December 2014 and November 2015.
powered with a sufficient sample size to assess the primary efficacy endpoint. The results
136
Both doses of ozanimod were well tolerated, with
A 2-year extension trial followed where ozanimod-treated
102
Patients were randomized (1.1:1) to once-
102,137
The study also concluded that ozanimod 0.92 mg
102
Treatment with ozanimod for 24 months resulted in
102
101
The study was adequately
234
https://t.me/med1917
Chemistry and Pharmacology of Drug Discovery
were similar to those of RADIANCE B. Both RADIANCE B and SUNBEAM trials
reported a reduction in the loss of whole-brain volume, cortical grey matter, and thalamic
volume with ozanimod (1) when compared to IFN β-1a. These results suggest a possible
role of ozanimod in protecting against structural changes associated with disease
progression over time. SUNBEAM also confirmed that both low and high-dose ozanimod
was as effective to IFN β-1a in reducing active disease in relapsing MS, with ozanimod
0.92 mg demonstrating numerically greater efficacy than Ozanimod 0.46 mg.
124
The
study found ozanimod was more effective than IFN β-1a in lowering the ARR and
lowering the number of new T2 lesions and GdE lesions over 12 months.
A post hoc analysis comparing the effects of ozanimod and IFN β-1a on
cognitive processing speed (CPS) in SUNBEAM study showed ozanimod had modestly
beneficial effects on CPS in relapsing MS participants. It improved Symbol Digit
Modalities Test (SDMT) scores at months 6 and 12. A more significant percentage of
Ozanimod-treated participants had clinically meaningful improvements in SDMT scores
vs IFN β-1a: 30.0% vs 22.2% at month 6 and 35.6%. vs 27.9% at month 12.
SUNBEAM study also reported TEAEs by 59.8% of patients on ozanimod 0.92
mg/d, 57.2% of patients on ozanimod 0.46 mg/d, and 75.5% patients on IFN β-1a. The
TEAEs that occurred in more than 5% of patients treated with ozanimod were
nasopharyngitis, upper respiratory tract infections and headache. No clinically significant
bradycardia or second or third-degree atrioventricular block was observed. No serious
108
opportunistic infections have been reported to date.
The long-term safety and efficacy of ozanimod in relapsing MS was studied in
the DAYBREAK open-label extension (OLE) trial. Patients with relapsing MS who
completed a phase 1–3 ozanimod trial were eligible for the open-label study of ozanimod
0.92 mg/d. The study characterizes safety and efficacy of ozanimod for up to 5 years and
up to 8 continuous years of exposure in patients with RMS. The overall safety and
tolerability profile of ozanimod was consistent with the phase 3 trials. MS clinical and
radiologic disease activity remained low in patients who received ozanimod 0.92 mg
continuously since the parent trials. Patients who switched to ozanimod 0.92 mg from
either IFN β-1a or ozanimod 0.46 mg experienced reductions in ARR and brain MRI
lesion
counts. The study found that the risks of oral herpes and herpes zoster didn’t
increase with longer ozanimod usage. COVID-19 cases during DAYBREAK were
largely nonserious and a vast majority of patients recovered from COVID-19 without
sequelae. Incidence of relapse after ozanimod discontinuation was low in DAYBREAK,
139
and none of the relapses resulted in persistent, severe disability.
Another phase III clinical trial ENLIGHTEN is currently ongoing to document
any changes in cognitive processing speed over 3 years as measured by the Symbol Digit
Modalities Test (SDMT) in adult participants with RMS who receive treatment with
140
ozanimod (1).
235
https://t.me/med1917
Chapter 11. Ozanimod (Zeposia)
5.2. Ozanimod to Treat Ulcerative Colitis
TOUCHSTONE was a randomized, double-blind, placebo-controlled phase II trial that
included a 5-week screening, 9-week induction (including an initial 7-day dose-escalation
period), 24-week maintenance and optional OLE period in patients with moderately to
severely active UC.
who received oral ozanimod 0.46 mg and ozanimod 0.92 mg once daily compared with
placebo after 8 weeks of induction therapy (14%, 16% vs 6% respectively) and an
additional 24 weeks of maintenance therapy (26%, 21% vs 6% respectively). Statistical
significance (P < 0.05) was observed for only ozanimod 0.92 mg during induction and for
both doses during maintenance. OLE study showed that for OLE patients who received
ozanimod 0.92 mg once daily, the observed Mayo scores decreased within 4 to 8 weeks
and those were maintained up to 200 weeks.
TRUENORTH was a 52-week, phase III, randomized, double-blind, placebocontrolled trial of ozanimod as induction and maintenance therapy in patients with
moderately to severely active UC. It is designed to further evaluate ozanimod 0.92 mg for
UC treatment. In the 10-week induction period, patients were assigned to receive
ozanimod or placebo. At 10 weeks, patients with a clinical response to ozanimod
underwent randomization to receive double-blind ozanimod or placebo for the
maintenance period (through week 52). Clinical remission was achieved by significantly
more patients who received ozanimod compared with placebo at weeks 10 (18.4% vs 6%,
P < 0.001) and 52 (37% vs 18.5%, P < 0.001). The results of TRUENORTH phase III
trial demonstrated that a once-daily oral formulation of ozanimod provided clinical
efficacy in patients with moderately to severely active UC. Treatment with ozanimod led
to significant improvements as compared with placebo, in the incidence of clinical
remission and in all key secondary clinical endoscopic and histologic end points at week
10 and 52. These results were observed in patients with active disease that had been
inadequately controlled by conventional agents.
Cancer, opportunistic infection, and macular edema were observed in patients
who received ozanimod, but the incidences were low. Non-serious infections were more
common with ozanimod than with placebo during the maintenance phase of the trial. The
incidences of elevated alanine aminotransferase levels were higher among patients who
received ozanimod than among those who received placebo. Liver events were mostly
mild or moderate in severity. Overall, the results were consistent with safety findings that
have previously been reported regarding ozanimod therapy in phase III trials involving
patients with MS.
141
Clinical remission was achieved by greater proportions of patients
141,142
143
40,143
236
https://t.me/med1917
Chemistry and Pharmacology of Drug Discovery
5.3. Ozanimod to Treat Crohn’s Disease
STEPSTONE was a 12-week, phase II, uncontrolled, multicenter trial in adults with
moderately to severely active CD. All patients began treatment with a 7-day dose
escalation of ozanimod hydrochloride (4 days on 0.25 mg daily followed by 3 days at
0.5 mg daily), followed by a daily dosage of ozanimod hydrochloride 1.0 mg for
11 weeks.
Crohn’s
remission, assessed by a blinded central reader, were achieved at estimates substantially
higher than anticipated based on results of a recent analysis following placebo
treatment.
Activity Score [GHAS] and Robarts Histopathology Index [RHI]) were also reduced
substantially from baseline at Week 12.
treatment benefit. The overall mean decrease from baseline in (Crohn’s Disease Activity
Index) CDAI score was −130.4.
safety profile to that in UC, with no new safety concerns identified. No clinically
important changes in heart rate were observed at treatment initiation, consistent with
previously reported findings in MS.
Based on the positive phase II results, a phase III program (YELLOWSTONE)
for ozanimod to treat CD was initiated in 2019 and is currently ongoing. The
YELLOWSTONE clinical trial was designed to assess the safety and efficacy of
ozanimod treatment for adults with moderately to severely active CD with inadequate
response or intolerance to other treatments.
144
A reduction from baseline in the mean Simple Endoscopic Score for
Disease (SES-CD) was reported at Week 12, and endoscopic response and
145
Additional objective measures of disease activity (Global Histologic Disease
146
Other endpoints were also consistent with a
In general, the study concluded that ozanimod was well tolerated, with a similar
144
40
6. Synthesis
In their patents, Rosen, Roberts, and their teams at Scripps reported a racemic synthesis
of ozanimod (1).
Amidoxime 3 was prepared from a benzonitrile substrate 2. The oxadiazole core was
constructed through the condensation of a benzoic acid derivative 4 with the amidoxime
substrate 3. This method served as the foundation for several subsequent approaches. In
the final step, the C‒N bond was formed via an S
starting material, yielding a racemic product. The enantiomer ozanimod (1) was isolated
by chiral HPLC separation to achieve 99% purity by weight.
147,148
The route was concise, involving only three steps (Scheme 1).
2 reaction using CC1084037 (5) as the
N
237
https://t.me/med1917
Chapter 11. Ozanimod (Zeposia)
Scheme 1. Racemic synthesis of ozanimod (1)
A Hungarian company, Egis Pharmaceuticals, patented the process for the
149
2).
production of a single enantiomer of ozanimod (1) in 2018 (Scheme
route takes advantage of enantiopure sulfonamide precursor, which is key to the
formation of C‒N bond with desired configuration in the diastereoselective imine
reduction step. The sulfonamide also assists in the subsequent amine alkylation step. In
the last step, hydrolysis in the acid liberates both the free amine and hydroxy group to
afford the final product 1.
The synthetic
Соседние файлы в папке Библиотека им академика М.И. Перельмана