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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5371_Библиотеки_им_академика_М_И_Перельмана
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crosses the basolateral membrane via the organic solute transporter alpha-beta (OstαOstβ) to feed into the portal vein and back to the liver for use in later digestive cycles.
Chemistry and Pharmacology of Drug Discovery
3. Early Inhibitors of the Ileal Bile Acid
Transporter
There have been many approaches to modulating bile acid levels including bile acid
sequestrants, direct dosing of secondary bile acids like ursodeoxycholic acid, or
modulation of receptors involved in bile acid synthesis like FXR
sequestrants, most medications in this space have historically mimicked cholesterol
structure.
In the pursuit of novel treatment methods for hypercholesterolemia, the
Burroughs Wellcome Company published preliminary work on a benzothiazepine
structure in 1995. Compound 2164U90 (12) was unveiled with an IC
the transport of taurocholic acid by human ileal brush border membrane vesicles.
They also discovered that the 2164U90 structure functions as a reversible competitive
inhibitor of the ileal bile acid transporter through a series of experiments with tritium
labeled taurocholic acid. In contrast to the practice of using cholesterol derivatives to
modulate bile acid levels, the discovery of this potent benzothiazepine scaffold for IBAT
inhibition offered a novel perspective in the field.
28
. Aside from bile acid
of 2 μM against
50
29, 30
4. Structure–Activity Relationship (SAR)
To follow up on compound 2164U90 (12), several teams explored the SAR for
benzothiazepine based IBAT inhibitors. In 2004, a team at the University of Missouri
worked on expanding the SAR for benzothiepine inhibitors related to 2164U90 (12).
Their early studies focused on increasing potency and identifying the number of chiral
31, 32
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centers necessary for activity in the thiepine ring. Through a seven-step synthesis to reach
thiepines 13 and 14, the chirality effects of the 3, 4, and 5 positions of the core ring
system were interrogated (Table 1).
Chapter 17. Odevixibat (Bylvay)
Compound R
(±)-13a H OH 0.28
(±)-13b OH H 4.8
(±)-14a H OH 2
(±)-14b OH H 37% at 10 μM
Table 1. Evaluation of the C3, 4, and 5 chiral centers
Both compounds 13a and 14a with cis confirmations between the C4 hydroxyl
and C5 phenyl ring outperformed their trans counterparts, 13b and 14b. Additionally,
between these two, cis orientation of the phenyl, hydroxyl, and C3 ethyl group further
boost the potency, with compound 13a giving an in vitro IC
IBAT.
From here, substitution patterns on benzo-fused ring were looked at (Table 2). It
was clear that substitution at the 7-position is preferred, compared to similar substitution
at the 8-position, with electron-donating amines outperforming electron-withdrawing
amide counterparts. There is also some inference as to binding pocket size found in their
series of bulkier alkyl amine-containing derivatives. Where the amine 17 and dimethyl
amine 18 occupy appropriate space in the binding pocket, hexylamine 19 is over 300-fold
less potent than 18. The same trend follows in amide derivatives 20 and 21.
1
R2 IBAT IC
of 0.28 μM against human
50
50
(μM)
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Chemistry and Pharmacology of Drug Discovery
Compound R
(±)-13a H 0.28
15 7-OMe 0.055
16 8-OH 0.09
17 7-NH2 0.068
18 7-NMe
19 7-NHC6H13 1.67
20 7-NHCO2CH2Ph 0.4
21 7-NHCOCH3 0.09
Table 2. Optimization of fused benzene ring substituents
From this point, the C3 stereocenter of 18 was amended to an achiral di-butyl
substitution to simplify the structure down to only two chiral centers with compound 22.
With the 5 nM compound 22 in hand, focus turned toward improving PK properties of
their lead.
2
IBAT IC
0.005
(μM)
50
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Chapter 17. Odevixibat (Bylvay)
To prevent undesirable systemic exposure, they worked on further developing
compound 22 by amending highly polar functionalities to the C5-phenyl ring to promote
intestinal localization. Dicarboxylic acid 23 and quaternary ammonium salt 8 (which
would later come to be known as maralixibat) improved the potency down to 2 and
0.28 nM, respectively, while eliminating systemic exposure to these compounds.
At the same time, AstraZeneca and its spinoff Albireo began pumping out
patents in the same space on benzothiazepine and benzothiadiazepine inhibitors bearing
33–35
peptide chains as the means of modulating PK properties.
the release of elobixibat (2), which despite its impressive 1.2 nM IC
28% inhibition of human IBAT in vivo at 0.156 μmol/kg dosage.
With these patents came
, only exhibited a
50
13
Many derivatives synthesized from elobixibat’s (7) core included short peptides
with 1–3 amino acids in length and all tended toward low nanomolar activity. Trending
once again toward improved gut localization with more heteroatoms for decreased
intestinal permeability, amending on 2-amino acid peptides became the most popular
option to simplify synthesis (Table
3).
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Chemistry and Pharmacology of Drug Discovery
Compound X R1 R2
IBAT IC
(nM)
50
Elobixibat (7) CH2 H 1.2
24 NH H 0.45
25 NH Me 0.2
26 NH CH2SMe 0.35
27 NH Me 0.3
Odevixibat (1) NH Et 0.16
Table 3. Optimization of peptide chain substituents
Comparing otherwise similar analogues, insertion of the sulfonamide
functionality into the benzothiazepine ring resulted in almost a 3-fold increase in potency
from elobixibat’s structure (2) to compound 24. At the R
position, various small alkyl
1
substituents were all well tolerated, with ethyl groups showing the best results. Finally,
swapping from an unsubstituted phenyl group at the R
the structure of odevixibat (1), showing an excellent 0.16 nM IC
IBAT activity at 0.156 μmol/kg dosage during in vivo mouse model studies.
position to a phenol leads us to
2
and 74% inhibition of
50
13
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Chapter 17. Odevixibat (Bylvay)
5. Pharmacokinetics and Drug Metabolism
Due to the extensive development efforts to ensure intestinal localization of odevixibat
(1), the drug has very minimal systemic exposure.36 Up to 83% of the initial dose is
excreted in feces. Doses of anywhere from 40 up to 120 μg/kg have no detectable plasma
concentrations in most patients. Following a 7.2 mg dosage, mean C
to be 0.47 ng/mL and mean AUC
was 2.19 ng*h/mL. Additionally, odevixibat (1) is
0–24 h
was determined
max
>99% protein bound and 97% of the excreted drug remains unmetabolized with monohydroxylation being the only detectable metabolite during in vitro studies. Its mean halflife after a single dose is 2.5 h.
It is also important to note that in patients with ABCB11 gene variants that
result in dysfunction or absence of bile salt export pump protein (BSEP), odevixibat (1)
may not be an effective treatment for PFIC.
6. Efficacy and Safety
During development, odevixibat (1), formulated as the sesquihydrate, performed well
across several bouts of in vitro and in vivo mouse model studies. Odebixibat (1) was not
found to inhibit any CYP isoforms, P-gp, BCRP, OCT2, MATE1, or MATE2K in vitro.
It also has no notable affinity for other bile acid transporters as IBAT is the only uptake
transporter for bile acids in the intestine. While the Ostα-Ostβ,
NTCP, and BSEP
transporters all recognize bile acids, they occur further downstream in enterohepatic
circulation and odevixibat (1) first inhibits IBAT prior to traveling further into
enterohepatic circulation.
Translating well into clinical trials, the safety and dosage or odevixibat (1) was
37
first assessed. Phase 1 studies enrolled 62 patients with PFIC type 1 or 2.
once daily dosages of 40 μg/kg
odevixibat (1), a mean 22.2% of patients reported
Following
significant reduction of pruritus over the 24-week trial over the placebo group. At
dosages of 120 μg/kg,
16.9% of patients reported significant improvement in pruritus
relative to placebo. The most reported adverse effects included diarrhea, elevation of
transaminase levels, serum bilirubin elevation, and fat-soluble vitamin deficiency. No
major adverse effects were reported in phase 1 studies.
An exploratory phase 2 trial included administration of 10–200 μg/kg daily
38
doses to 20 patients.
Similar endpoints were reported, as in phase 1 trials. Primary
adverse events included liver test abnormalities such as elevated ALT, AST, as well as
direct and total bilirubin levels. Four patients re-enrolled in a second-dose level along
with seven others. Serum bile acid levels were reportedly reduced in all cohorts.
Reductions in pruritus of 43% to 98% for 11 of the 13 enrolled patients were reported,
providing further support for odevixibat (1)’s efficacy in vivo.
37
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Chemistry and Pharmacology of Drug Discovery
Rapid phase 3 trials39 found a similar reduction in pruritus and greater than 70%
reduction in serum bile acid levels in 33% of patients over a 24-week period. Following
these results, odevixibat (1) was granted its first FDA approval for treating pruritus in
PFIC patients ages 3 months and up by the FDA in 2021. Similar clinical evaluations
40
took place to assess efficacy and safety in patients with ALGS in 2023.
Leading directly
into a second FDA approval for pruritus in patients 12 months and up with ALGS,
odevixibat (1) became the first approved IBAT inhibitor for PFIC and the second for
ALGS, following maralixibat (8).
7. Synthesis
The synthesis of odevixibat (1) occurs through an 11-step linear synthesis
41, 42
beginning
with functionalization and cyclization of the core benzothiadiazepine ring system.
Following, peripheral functionalization to carry out methanethiol substitution and
sequential amide coupling steps to form the chiral dipeptide chain completes the
synthesis to give odevixibat (1) in straightforward fashion.
Starting from commercially available thiol 28, bromination and disulfide
formation gives dibromide 29 in 19% yield over two steps. Following oxidative
chlorination of 29, the resulting sulfonyl chloride 30 is prepped for a two-step cyclization
to form the core thiadiazepine motif.
Selective addition of the primary amine of 31 into sulfonyl chloride 30 gives the
tethered sulfonamide 32. The difficulty in this step likely originates from attempting
addition of a diamine substrate into the electrophilic system of 30 which can potentially
react at three different places, through the sulfonyl chloride or S
Ar at either bromide.
N
Despite the complexity of this step, sulfonamide 32 can still be isolated to proceed with
the synthesis.
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The intramolecular Ullmann-type coupling of 32 proceeds in a moderate 52%
yield to give cyclized benzothiadiazepine 33. With the core of the molecule complete,
only peripheral modification and amending of the peptide chain are left. The most
difficult steps are out of the way with isolation of the tetrabrominated disulfide 29 from
the first step and selective addition with the sterically hindered primary amine 31.
Chapter 17. Odevixibat (Bylvay)
To continue functionalizing the periphery, the bromide of 33 undergoes SNAr
reaction with sodium methanethiolate to give compound 34. The crude mixture of 34 is
then resuspended in acetonitrile to complete the coupling with ethyl bromoacetate to give
ethyl ester 35 in 58% yield over two steps. Saponification of 35 gives free acid 36.
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Carboxylic acid 36 can then efficiently couple with amino acid 37 under TBTUcatalyzed conditions to give t-butyl ester 38. A second TBTU-catalyzed coupling of ester
38 with amino acid 39 and a TFA deprotection of the resulting t-butyl protected dipeptide
gives odevixibat (1) in a final yield of 66% over the last two steps.
Chemistry and Pharmacology of Drug Discovery
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While all the steps in odevixibat’s (1) synthesis appear straightforward at first
glance, the difficulty arises when considering isolation of a single desired product from
an array of competing products and isomers in the early steps. Through careful setup and
cyclization of the core ring system in five concise steps, the peripheral functionalities can
easily be amended to complete the synthesis in a facile manner.
Chapter 17. Odevixibat (Bylvay)
8. Summary
The development process of the ileal bile acid transporter odevixibat (1), was an arduous
but inspiring one. Through the effort of many groups, the discovery of a simple but
effective benzothiazepine scaffold decades ago was able to develop into something much
more fruitful. The rigorous efforts made to expand our understanding of bile acid
function and transport in the body have made the development of such highly selective
and potent inhibitors possible.
Reflecting on the milestones and achievements in odevixibat (1)’s development
process, it is important to highlight the many improvements and iteration cycles made
along the way. Starting from the discovery of the scaffold, derived from compound
2164U90 (12), early studies on SAR and chirality made significant progress toward
validating benzothiazepine-based drugs for bile acid-related diseases. Later PK studies
using ammonium salts, carboxylates, and peptide chains to target intestinal localization
helped further pave the road toward the clinical successes witnessed later. Together, these
achievements brought forth a first-in-class treatment option for two rare and debilitating
genetic disorders, PFIC and ALGS.
Odevixibat (1), being the first IBAT inhibitor to reach FDA approval in 2021
along with its second approval in 2023, paved significant ground in the landscape of
medicinal chemistry. As such, the success of Albireo’s IBAT inhibitor program has done
much to spur the development of new projects in cholestasis research, with many more,
sure to follow.
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