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_5371_Библиотеки_им_академика_М_И_Перельмана
.pdf
338
https://t.me/med1917
made during hit-to-lead efforts and focus on fine-tuning these leads to further improve
whole blood potency, mitigate a potential cardiovascular liability while allowing for a
lower projected human dose.
As the strategic replacement of the 2-aminopyridine side chain with the
cyclopropyl carboxamide successfully reduced hERG affinity and the deuteromethyl
group binding to the atypical “alanine pocket” of TYK2 JH2 furnished high
amide
selectivity while also blocking an N-demethylation metabolic pathway, modifications
centered around the aryl methyl sulfone group. X-ray crystal structures of sulfone
analogues such as 18 bound to TYK2 JH2 proved very revealing.
interactions already described, of note was the presence of a structural water molecule
aiding indirect hydrogen bonds between the second sulfone oxygen of 18 with Arg738 and
Gln597 of the P-loop region (Figure
investigation to replace an energetically disfavored water molecule and form an additional
direct hydrogen bond interaction with the protein, was pursued
Chemistry and Pharmacology of Drug Discovery
28
13). To further improve potency, a targeted
.
In addition to key
Figure 13. X-ray crystal structure of 18 bound with TYK2 JH2, highlighting the key
hydrogen bond interactions within the ligand binding site and the observed structural
Investigating moieties that could replace the water molecule while also lowering
PSA led to initial SAR studies being pursued on a prior compound within the pyridine-3carboxamide series. Replacement of the methyl sulfone group with a methoxy substituent
yielded a compound that had a lower PSA and although ~five-fold potency was lost, this
change formed the basis of further SAR efforts. A review of modelling results revealed
that introduction of hydrogen bond accepting groups ortho to the C2′ methoxy (C3′
position) could replace the structural water and form a direct hydrogen bond with the
water (PDB ID: 6NZR)
339
https://t.me/med1917
Chapter 15. Deucravacitinib (Sotyktu)
Arg738 side chain. This led to a comprehensive SAR investigation of C3′ amides that
provided some key findings: the C2′ methoxy group was critical, as its removal led to a
dramatic loss in potency and the carbonyl O of the C3′ amides formed a direct hydrogen
bond with Arg738. Despite good potency and validation of the water replacement strategy,
the amides suffered from metabolic instability and permeability issues.
To address these, preparation of a variety of five-membered heterocycles that
contained a heteroatom at the ortho position to the ring connection were found to
successfully mimic the hydrogen bond interaction with Arg738 made by the carbonyl O of
C3′ amides. Triazole 19 exhibited remarkable potency and exemplified >1000-fold
the
selectivity for TYK2 JH2 in an in-house 260 kinase panel. However, it was found to be a
modest hERG inhibitor (31 μM IC50) (Figure 14).
Figure 14. Structure and associated in vitro data for compound 19
In an attempt to mitigate this potential cardiac liability, the C6 cyclopropyl amide
side chain was reintroduced and as anticipated, compound 20 gave reduced hERG
inhibition and excellent hWB potency (Table 2). The deuterated methyl amide 21 was
made to prevent in vivo formation of the primary amide but unfortunately it exhibited poor
exposure which was attributed to the reduced permeability (Table 2). This issue was
overcome by making the
pyridazine variant of 21. This led to 1, which unknowingly at the
time, would eventually become deucravacitinib!
Compound 1 maintained excellent potency in hWB and exhibited functional
selectivity in hWB of ~47-fold against JAK1/JAK2 (IL-6 IC
against JAK1/JAK3 (IL-2 IC
= 1900 nM), and high kinome selectivity against 249
50
= 609 nM), ~150-fold
50
kinases. In vitro ADME and in vivo pharmacokinetics in rodent and higher species revealed
high stability in liver microsomes (T
leading to much improved exposure (C
> 120 min), significantly improved permeability
1/2
= 7500 nM for 1 vs 310 nM for 21), low overall
max
drug–drug interaction (DDI) risk and no significant hERG inhibition in the flux assay
(IC50 > 80 μM) (Table 2). With it also demonstrating robust efficacy in murine models of
TYK2
JH2
(IC
50
,
nM)
IFNα
(IC
50
,
nM)
hWB
(IC
50
,
nM)
hERG
flux
(IC
50
,
μM)
340
https://t.me/med1917
Chemistry and Pharmacology of Drug Discovery
psoriasis, lupus nephritis, and IBD, 1 was selected as a potential candidate for
28
advancement.
20 C CH
1
R
X R
2
0.7 14 16 93 23 >80
3
MLM
(%
rem)
Caco-2
(nm/sec)
21 C CD3 0.3 8 13 89 <15 >80
1 N CD3 0.2 5 13 89 70 >80
Table 2. In vitro data for select analogues from C3′ N-methyl triazole series
The proposed binding mode was confirmed from a solved X-ray structure of 1
bound to TYK2 JH2, reinforcing key interactions that have already been described (Figure
15). The observed increase in potency is most probably due to the C2′ methoxy forming a
direct hydrogen bond with the conserved Lys642. Remarkably, the des-methoxy variant of
1 was determined to be ∼100-fold less potent in TYK2 JH2 binding affinity. Replacement
of the structural water molecule occurred through a direct hydrogen bond engagement with
Arg738 of the N-2 triazole nitrogen, as thoughtfully designed.
28
341
https://t.me/med1917
Chapter 15. Deucravacitinib (Sotyktu)
Figure 15. X-ray crystal structure of 1 bound with TYK2 JH2 showing key interactions
(PDB ID: 6NZP)
4. Pharmacokinetics and Drug Metabolism
In preclinical pharmacokinetic studies of intravenously (iv) and orally administered (po)
deucravacitinib (1) across multiple species, the low rate of metabolism observed in the
microsomal assays (T
excellent exposures, and high bioavailability (%F > 85) in mouse, dog, and monkey.
Circulating primary amide metabolite formation from N-dealkylation of the deuteromethyl
amide of 1 was near the lower limits of detection (<2 nM) in these studies, consistent with
deuteration serving as an effective strategy for blocking of this metabolic pathway.
Following oral administration in humans, deucravacitinib’s plasma Cmax and
AUC increased dose proportionally over a 3–36 mg dose range (0.5- to 6-fold the approved
recommended dosage) in healthy subjects.
subjects, the accumulation of deucravacitinib was <1.4-fold. The PK of deucravacitinib
and its active demethylated metabolite, BMT-153261, were comparable between healthy
subjects and subjects with psoriasis. The steady state C
following administration of 6 mg once daily were 45 ng/mL and 473 ng h/mL,
respectively. The steady state C
BMT-153261, following administration of 6 mg once daily were 5 ng/mL and 95 ng h/mL,
respectively.
The absolute oral bioavailability of deucravacitinib was 99% and the median T
ranged from 2 to 3 h in healthy subjects. No clinically meaningful differences in the
pharmacokinetics were observed after administration of a high-fat, high-calorie meal. C
and AUC of deucravacitinib when administered with food were decreased by
> 120 min) translated into low to modest in vivo clearance rates,
1/2
29
Following once-daily dosing in healthy
and AUC24 of deucravacitinib
max
and AUC24 of the active deucravacitinib metabolite,
max
28
max
max
342
https://t.me/med1917
Chemistry and Pharmacology of Drug Discovery
approximately 24% and 11%, respectively, and T
was prolonged by 1 h. C
max
and AUC
max
of BMT-153261 when administered with food were decreased by approximately 23% and
10%, respectively, and T
was prolonged by 2 h.29
max
The volume of distribution of deucravacitinib at steady state was 140 L. Plasma
protein binding of deucravacitinib was 82–90% and its blood-to-plasma concentration ratio
was 1.26. The terminal half-life of deucravacitinib was 10 h. The renal clearance of
29
deucravacitinib ranged from 27 to 54 mL/min.
Deucravacitinib is metabolized by cytochrome P-450 (CYP) 1A2 to form major
metabolite BMT-153261. Deucravacitinib is also metabolized by CYP2B6, CYP2D6,
carboxylesterase (CES) 2, and uridine glucuronyl transferase (UGT) 1A9. Although the
active deucravacitinib metabolite, BMT-153261, has comparable potency to the parent
drug, its circulating exposure accounts for approximately 20% of the systemic exposure of
29
all drug-related components.
5. Efficacy and Safety
In preclinical studies in mice, deucravacitinib (1) was determined to be efficacious against
both type I IFN, IL-12, and IL-23-dependent pathobiology. The in vivo efficacy from orally
administered 1 was demonstrated in multiple murine models of psoriasis, colitis, and lupus
and correlated well with the whole blood IC
was at least as effective as the blocking antibody controls used in these studies.
In humans, the efficacy and safety of deucravacitinib (6 mg once daily) was
evaluated in two multinational, multicenter, randomized, double-blind, placebo- and active
comparator-controlled 52-week Phase 3 clinical trials, POETYK PSO-1 (NCT03624127)
and POETYK PSO-2 (NCT03611751).
older with moderate-to-severe plaque psoriasis and were candidates for phototherapy or
systemic therapy. Participants had a body surface area involvement of ≥10%, a Psoriasis
Area and Severity Index (PASI) score ≥ 12, and a static Physician’s Global Assessment
30
(sPGA) ≥ 3 (moderate or severe).
Efficacy was assessed in POETYK PSO-1 (664 enrolled patients) and POETYK
PSO-2 (1,020 enrolled patients) randomized to either Sotyktu (6 mg once daily), placebo,
®
or Otezla
(apremilast) (30 mg twice daily). The two co-primary endpoints of both trials,
assessed at week 16 vs placebo, were the proportion of patients who achieved at least a
75% improvement in PASI scores from baseline (PASI 75) and the proportion of patients
who achieved a sPGA score of 0 (clear) or 1 (almost clear) with at least a 2-grade
improvement from baseline (Table
3).
Key secondary endpoints assessed at week 16 and week 24, that compared
Sotyktu and placebo, included the percentage of subjects who achieved PASI 75, PASI 90
and sPGA 0/1 (Table 3).30 As shown, response rates across all primary and secondary
value coverage over the dosing intervals and
50
30
All enrolled subjects were 18 years of age and
30
28
Placebo
(n = 166)
Otezla 30 mg
(n = 168)
Placebo
(n = 255)
Otezla 30 mg
(n = 254)
343
https://t.me/med1917
Chapter 15. Deucravacitinib (Sotyktu)
endpoints at both 16 and 24 weeks were highest for deucravacitinib, demonstrating its
superiority over both placebo and twice-daily Otezla for the treatment of patients with
moderate-to-severe plaque psoriasis.
POETYK PSO-1 (n = 664) Results at Week 16 and Week 24
Endpoint
Time Sotyktu 6 mg
(n = 330)
PASI 75
PASI 90
sPGA 0/1
Week 16 58%
a
Week 24 69% —
Week 16 36% 4% 20%
Week 24
Week 16 54%
42% — 22%
a
Week 24 59% —
13%
7%
a
35%
38%
a
32%
31%
POETYK PSO-2 (n = 1020) Results at Week 16 and Week 24
Endpoint
Time Sotyktu 6 mg
(n = 511)
PASI 75
Week 16 53%
a
a
9%
40%
Week 24 58% — 38%
PASI 90
sPGA 0/1
Week 16 27% 3% 18%
Week 24
Week 16 50%
32% — 20%
a
9%a 34%
Week 24 49% — 30%
a
Co-primary endpoints for POETYK PSO-1 and POETYK PSO-2 at Week 16.
Table 3. Efficacy results in adults with moderate-to-severe plaque psoriasis from
30
POETYK PSO-1 and POETYK PSO-2 clinical trials at Week 16 and Week 24
Responses persisted through Week 52, as 78% (151/194) of patients who achieved
an sPGA 0/1 response at week 24 maintained their response at week 52. Amongst the
patients who achieved PASI 75 and PASI 90 with Sotyktu at Week 24, 82% (187/228) and
74% (103/140) respectively, maintained their response at Week 52, in POETYK PSO-1.
In POETYK PSO-2, 80% (119/148) of patients who continued on Sotyktu maintained PASI
75 response compared to 31% (47/150) of patients who were withdrawn from Sotyktu.
Another noteworthy finding was in patients that transitioned over from placebo to Sotyktu
treatment at week 16 had clinical
who received continuous Sotyktu treatment from day 1.
At week 16, In the POETYK PSO trials, the most common adverse reactions
(≥1% and higher than placebo) in patients on Sotyktu were upper respiratory infections
(19.2%), blood creatine phosphokinase increase (2.7%), herpes simplex (2.0%), mouth
ulcers (1.9%), folliculitis (1.7%), and acne (1.4 %). The frequency of serious adverse
31
responses at week 52 that were comparable to patients
31
344
https://t.me/med1917
events during weeks 0-16 was lowest in the Sotyktu group (2.1% vs 5.5% with placebo and
2.4% with Otezla). In addition, discontinuation due to adverse reactions was encountered
for 2.4% of patients on Sotyktu, 3.8% of patients on placebo, and 5.2% of patients on
30
Otezla.
Chemistry and Pharmacology of Drug Discovery
6. Synthesis
6.1. Discovery Synthesis Route
The general route to make the N-methyl nicotinamides and N-methyl pyridazine-3carboxamides (not shown) employed established chemistry and proved to be highly
versatile, lending itself well for both SAR exploration and for larger scale preparation of
key compounds that were needed for advanced preclinical testing.
The synthesis of core pyridazinone intermediate 2725 initiated with diazo transfer
to diethyl malonate 22 to provide 24. Subsequent chemistry involved a diaza-Wittig
reaction followed by hydrolysis and saponification to provide crude acid diol 25.
Chlorination with POCl
trapped in situ with the methyl-d
provide amide 27 (Scheme
furnished the trichloro-intermediate 26 that was subsequently
3
-amine hydrochloride in the presence of Hunig’s base to
3
1).
Scheme 1. Synthesis of intermediate 27
345
https://t.me/med1917
The synthesis of 1 commenced with methylation of commercially available
methyl-2-hydroxy-3-nitrobenzoate 28 (Scheme
ester to ammonia afforded amide 29. Incorporation of the triazole motif was achieved
through reaction of 29 with DMF-DMA followed by condensation with hydrazine hydrate
to afford 30. Methylation of the triazole with methyl iodide in the presence of potassium
carbonate afforded a 2:1 mixture of the desired regioisomer 31 and undesired regioisomer
32, respectively. Separation of the regioisomers was attained by supercritical fluid
chromatography (SFC) to afford the desired isomer 31 in 67% overall yield. It was found
that a significant improvement in the regioselectivity (~8:1) in favor of the desired isomer
31 could be accomplished by replacing potassium carbonate with potassium
hexamethyldisilazide as the base and THF instead of DMF, as the solvent. The crude
product enriched in the desired isomer could be crystallized to afford isomerically pure 31,
eliminating the need to separate the isomers by SFC on a larger scale.
Pure 31 was subjected to standard palladium-catalyzed hydrogenation conditions
for the nitro group reduction to yield aniline 33 in 92% yield. Subsequent coupling to
pyridazine core intermediate 27 using lithium
the penultimate intermediate 34 in 66% yield. Initial Buchwald−Hartwig coupling of 34
with cyclopropyl amide 35 using XantPhos as the palladium ligand afforded 1 in a modest
46% yield. This was significantly improved by replacing the XantPhos ligand with 1,1′bis(dicyclohexylphosphino)ferrocene (dppf) and switching out the cesium carbonate base
aqueous potassium triphosphate. These adjusted conditions allowed a lower reaction
with
temperature and
quantities of 1 for advanced preclinical studies (Scheme
Chapter 15. Deucravacitinib (Sotyktu)
28
2).
Subjecting the intermediate methyl
hexamethyldisilazide as the base afforded
afforded an improved 76% yield enabling preparation of multigram
28
2).
346
https://t.me/med1917
Chemistry and Pharmacology of Drug Discovery
Scheme 2. Discovery synthesis of deucravacitinib (1)
347
https://t.me/med1917
Chapter 15. Deucravacitinib (Sotyktu)
6.2. Process Development Route
Anticipating several metric tons of commercial API to be needed over the lifetime of a
successfully marketed drug, a thorough evaluation of the discovery chemistry route was
undertaken. Although the synthesis was modular and enabled preparation of sufficient
material to support SAR studies, several liabilities in this first-generation route were
identified
32
:
(a) Expensive, low-yielding synthesis of 33. This was ascribed to the poor
inherent regioselectivity in the triazole methylation.
(b) Poor yield in the deuteromethyl amide formation step. This was mainly
due to the inherent instability of the trichloro-intermediate 26, as
significant decomposition was encountered during the work-up of the
chlorination reaction. This low yield necessitated a large excess of
expensive trideuteromethyl amine (11 equivalents per equivalent of 1).
(c) Poor Yield in the API step. With the use of a palladium catalyst in the
last step, remediation efforts accounted for the poor yield. Due to
Nitrogen-rich 1 being an excellent metal chelator, multiple aqueous
washes, a resin treatment, and a recrystallization with methanol were
required to afford 1 with acceptable levels of residual palladium.
Efforts to devise new routes to 1 were initiated with cost and sustainability at the
forefront of route planning. Due to the simple connectivity of 1, the number of potential
routes was limited. It was envisioned that the central bis-aminoacylpyridazine core could
be derived from three sequential nucleophilic displacements to form three new C‒N bonds
(Figure 16). Initial route design efforts focused on trying to identify the potential order of
formation for these three C‒N bonds, considering the expected cost of the three nitrogen
nucleophiles. With the cost of trideuteromethylamine
was reasoned that the ideal route would incorporate amidation with trideuteromethylamine
in the final step. This would avoid the use of a Pd catalyst in the API step, helping to solve
the residual metal control issue. With respect to formation of the pyridazine C‒N bonds,
earlier studies revealed that much faster substitution took place at the C4 position over the
C6 position. Armed with this information, the planned general synthetic strategy would
incorporate the aniline fragment first, the cyclopropanecarboxamide fragment second,
followed by the trideuteromethyl amide last (Figure 16).
plaguing the discovery synthesis, it
Соседние файлы в папке Библиотека им академика М.И. Перельмана