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_5892_Библиотеки_им_академика_М_И_Перельмана
.pdf
378
https://t.me/med1917
2. FDA approves new treatment for hypoactive sexual desire disorder in
3. Dooley, E.; Melanie, M.; Clayton, A. Flibanserin: from bench to
4. Clayton, A. The pathophysiology of hypoactive sexual desire disorder
5. Stahl, S.; Sommer, B., Allers, K. Multifunctional pharmacology of
6. Katz, M.; DeRogatis L.; Ackerman, R.; Hedges, P.; Lesko, L.; Garcia,
7. Yuan, X.; Tao, Y. Ligands for melanocortin receptors: beyond
8. Shou, Y.; Yu, B.; Liu, H. New drug approvals for 2019: synthesis and
9. Vyleesi vs Addyi: What is the difference?
10. Cone, R. Studies on the physiological functions of the melanocortin
11. Yanik, T.; Durban, S. Specific functions of melanocortin 3 receptor
12. Wolf Horrell, E.; Boulanger, M.; D'Orazio, J. Melanocortin 1 receptor:
13. Jégou, S.; Cone, R.; Eberlé, A.; Vaudry, H. Chapter-111.
14. Palatin Technologies. https://palatin.com/press_releases/palatin-
Chemistry and Pharmacology of Drug Discovery
(ISSWSH) expert consensus panel review. Mayo Clin Proc. 2017,
92(1), 114–128.
premenopausal women, U.S. Food & Drug Administration.
https://www.fda.gov/news-events/press-announcements/fda-approvesnew-treatment-hypoactive-sexual-desire-disorder-premenopausal-
. Released June, 2019.
women
bedside. Sex. Med. Rev. 2017, 5, 461–469.
in women. Int. J. Gynaecol. Obstet., 2010, 10 (1), 7–11.
flibanserin: possible mechanism of therapeutic action in hypoactive
sexual desire disorder. J. Sex. Med. 2011, 8, 15–27.
M.; Sand, M. Efficacy of flibanserin in women with hypoactive sexual
desire disorder: results from the BEGONIA trial. J. Sex. Med. 2013, 10,
1807–1815.
melanocyte-stimulating
Biomolecules 2022, 12, 461–469.
clinical applications. Eur. J. Med. Chem. 2019, 205, 1–5.
https://www.drugs.com/medical-answers/vyleesi-addyi-difference3501189/
system. Endocr. Rev. 2006, 27(7), 736–749.
(MC3R). J. Clin. Res. Pediatr. Endocrinol. 2023, 15 (1), 1–6.
structure, function, and regulation. Front. Genet. 2016, 7, 1–16.
Melanocortins. Handbook of Biologically Active Peptides, Elsevier
Inc., 2013, 838–844.
technologies-announces-mutual-termination-of-license-agreementwith-amag-pharmaceuticals-for-vyleesi-2/
. Last updated Feb. 2023.
hormones and adrenocorticotropin.
. Released July, 2020.
379
https://t.me/med1917
15. Molinoff, P.; Shadiack, A.; Earle, D.; Dimond, L. PT-141: a
16. Shadiack, A.; Sharma, S.; Earle, D.; Spana, C.; Hallam, T.
17. Clayton A.; Lucas, J.; Jordan, R.; Spana, C.; Pfaus, J. The neurobiology
18. Pfaus, J.; Kippin, T.; Coria-Avila, G. What can animal models tell us
19. Berna, I.; Oktar, K. The actions of the α-melanocyte stimulating
20. Hadley, M.; Dorr, R. Melanocortin peptide therapeutics: historical
21. Sawyer, T.; Sanfilippo, P.; Hruby, V.; Engel, M.; Heward, C.; Burnett,
22. Luger, T.; Bohn, M. An α-MSH analog in erythropoietic
23. Al-Obeidi, F.; Castrucci, A.; Hadley, M.; Hruby, V. Potent and
24. Al-Obeidi, F.; Hadley, M.; Pettitt, B.; Hruby, V. Design of a new class
25. Hadley, M. Discovery that a melanocortin regulates sexual functions in
26. Hedlund, P. PT-141 palatin. Curr. Opin. Invest. Drugs, 2021, 26 (10),
27. Bremelanotide. https://go.drugbank.com/drugs/DB11653. Accessed
28. Diamond, L.; Earle, D.; Heiman, J.; Rosen, R.; Perelman, M.; Harning,
29. Clayton, A. H.; Lucas, J.; DeRogatis, L. R.; Jordan, R. Phase I
Chapter 16. Bremelanoide (Vyleesi)
melanocortin agonist for the treatment of sexual dysfunction. Ann. N. Y.
Acad. Sci. 2003, 994, 96–102.
Melanocortins in the treatment of male and female sexual dysfunction.
Curr. Top. Med. Chem. 2007, 7, 1137–1144.
and efficacy of bremelanotide in HSDD. J. Sex. Med. 2017, 14, E95.
about human sexual response? Annu. Rev. Sex Res. 2003, 14, 1–63.
hormone (α-MSH) in inflammatory conditions. Marmara Med. J. 2001,
14 (2), 113–118.
milestones, clinical studies and commercialization. Peptides 2006, 27,
921–930.
J.; Hadley, M. 4-Norleucine, 7-D-phenylalanine-alpha-melanocytestimulating hormone: a highly potent alpha-melanotropin with
biological activity. PNAS 1980, 77 (10), 5754–5758.
protoporphyria. J. Infect. Dis. 2015, 135, 929–931.
prolonged acting cyclic lactam analogues of α-melanotropin: design
based on molecular dynamics. J. Med. Chem. 1989, 32, 2555–2561.
of superpotent cyclic α-melanotropins based on quenched dynamic
simulations. JACS 1989, 111, 3413–3416.
male and female humans. Peptides, 2005, 26 (10), 1687–1689.
456–462.
December, 2021.
R. An effect on the subjective sexual response in premenopausal
women with sexual arousal disorder by bremelanotide (PT-141), a
melanocortin receptor agonist. J. Sex. Med. 2006, 3 (4), 628–638.
randomized placebo-controlled, double-blind study of the safety and
380
https://t.me/med1917
30. Clayton, A.; Altof, S.; Kingsbery, S.; DeRogatis, L.; Kroll, R.;
31. Kingsberg, S.; Clayton, A.; Portman, D.; Willams, L.; Krop, J.; Jordan,
32. Rosen, R.; Diamond, L.; Earle, D.; Shadiack, A.; Molinoff, P.
33. https://www.accessdata.fda.gov/drugsatfda_docs/ label/2019/
34. Flora, D.; Mo, H.; Mayer, J.; Khan, M.; Yan, L. Detection and control
35. Blood, C.; Shadiack, A.; Bernstein, J.; Herbert, G. Compositions and
36. Liao, Z.; Yang, Y. Solid phase synthesis of bremelanotide. Patent
37. Yan, L.; Wang, B.; Li, J.; Jin, Y.; Wang, J.;Yang, Z. A synthetic
38. Spielmans, G. Reanalyzing phase III bremelanotide trials for
Chemistry and Pharmacology of Drug Discovery
tolerability of BMT coadministered with ethanol in healthy male and
female participants. Clin. Ther. 2017, 39, 514–526.
Goldstein, R.; Kaminetsky, J.; Spana, C.; Lucas, J.; Jordan, R.;
Portman, D.; Bremelanotide for female sexual dysfunctions in
premenopausal women: a randomized, placebo-controlled dose-finding
trial. Womens Health 2016, 12 (3), 325–337.
R.; Lucas, J.;Simon, J. Bremelanotide for the treatment of hypoactive
sexual desire disorder. OBGYN 2019, 134 (5), 899–908.
Evaluation of the safety, pharmacokinetics and pharmacodynamic
effects of subcutaneously administered PT-141, a melanocortin
receptor agonist, in healthy male subjects and in patients with an
inadequate response to Viagras. Int. J. Impot. Res. 2004, 16, 135–142.
210557s000lbl.pdf
of aspartimide formation in the synthesis of cyclic peptides. Bioorg.
Med. Chem. Lett. 2005, 15, 1065–1068.
methods for sexual dysfunction. Patent US6794489B2, 2004.
CN101857629, 2010.
method for bremelanotide. Patent CN106589111A, 2017.
“hypoactive sexual desire disorder” in women. JSR 2021, 58, 1–20.
. Revised June 2019.
`
https://t.me/med1917
17
________________________________________________________________________________
Odevixibat (Bylvay): A Selective Inhibitor of
the Ileal Bile Acid Transporter
Andrew Outlaw and
Timothy A. Cernak
Much work has been done in recent years for developing novel treatment options for
orphan diseases. One recent case is that of Albireo Pharma’s Ileal bile acid
(IBAT) inhibitor odevixibat (1). As of 2021, odevixibat (1) has been approved by the
FDA as a first-in-class treatment option for pruritus in patients 3 months of age and older
with progressive familial intrahepatic cholestasis (PFIC). Following the 2023 acquisition
of Albireo by Ipsen, odevixibat (1) has also been approved to treat pruritus in patients 12
months and up with Alagille syndrome (ALGS). Odevixibat (1) is currently marketed
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.
transporter
382
https://t.me/med1917
under the commercial name Bylvay and sold as daily oral pellets or capsules for patient
populations affected by cholestatic liver disease.
The road toward safe and effective treatment options for cholestasis-inducing
disorders such as PFIC and ALGS is one lined with many hurdles. Cholestasis treatments
that properly balance efficacy while still managing adverse effects have largely remained
elusive. While a host of treatment options exist for managing cholestasis, if the adverse
effects of a treatment match the severity of the symptoms it aims to alleviate, the very
point of the treatment is lost for many. The approval of odevixibat (1) marks a significant
hallmark in treating cholestatic liver disease for its efficacy and general tolerability, as
well as its validation of targeting inhibition of the ileal bile acid transporter mechanism.
Chemistry and Pharmacology of Drug Discovery
1. Background
383
https://t.me/med1917
Chapter 17. Odevixibat (Bylvay)
Historically, medications for cholestatic liver disease include first-line treatment with the
bile acid sequestrant cholestyramine (2), the antimycobacterial second-line treatment
rifampicin (3), and alternative options like the μ-opioid receptor antagonists naltrexone
(4) or naloxone (5) or the selective serotonin re-uptake inhibitor (SSRI) sertraline (6).
The glaring issue with many of these options lies in poor palatability and patient
compliance due to adverse effects like gallstone formation, hepatitis, vomiting, or loss of
2–5
control of pain.
Ileal bile acid transport inhibitors were largely considered experimental
treatments prior to the recent development of IBAT inhibitors. Albireo’s odevixibat (1)
and elobixibat (7) along with Mirum Pharmaceutical’s maralixibat (8) present compelling
6–8
cases for treating cholestasis via modulation of bile acid reuptake.
IBAT inhibitors
work to lower the bile acid pool in the liver by preventing reuptake of bile acids in the
9
intestinal ileum via competitive inhibition of IBAT.
Thus bile acid load in the colon
increases, preventing bile acids recirculating back into the liver.
Odevixibat (1) is a “Me-Too” drug based on modification of the IBAT inhibitor
10
elobixibat (7) earlier developed by Albireo.
While elobixibat (7) showed a promising
early example of the benzothiazepine scaffold for IBAT inhibition, it never completed
11,12
clinical trials in the United States.
Instead, Albireo came to a licensing agreement
with Ajinomoto Pharmaceuticals to market the drug in Japanese and Asian markets in
2012.
1
384
https://t.me/med1917
Chemistry and Pharmacology of Drug Discovery
Picking back up on the benzothiazepine structure of elobixibat in the late 2010s,
Albireo made further modification of the peripheral structure of elobixibat (7) to include
alteration of the core sulfone to a sulfonamide along with a chiral ethyl chain and
phenolic hydroxyl group. These alterations give the final odevixibat (1) structure with
improved potency for IBAT in humans (IC
13
tolerability and safety profile.
Completing clinical trials in the United States and
= 0.16 nM vs 1.2 nM) while maintaining its
50
receiving FDA approvals in 2021 and 2023, odevixibat (1) is considered a first-in-class
14
medication for treatment of cholestatic pruritus resulting from PFIC and ALGS.
As we
are now done outlining the history of drugs for treating cholestatic liver disease, we now
dive into the pharmacology of ileal bile acid transport inhibitors.
2. Pharmacology
PFIC and ALGS are both disorders that affect the enterohepatic flow of bile in the body.
PFIC is a hereditary disorder that affects the ability of liver cells to properly secrete bile
within the liver.
development of too few bile ducts to export bile out of the liver.
cholestasis, or reduced flow of bile out from the liver, in neonates. Proper diagnosis and
treatment within the first several months of life is often necessary to prevent scarring and
potential failure of the liver.
2.1. Enterohepatic Circulation of Bile Acids
Bile is a physiological solution released from the liver that helps to separate the nutrients
from the waste in the digestive system. Bile is primarily composed of bile acids and bile
acid-conjugates derived from cholesterol (9) such as cholic acid (10) and taurocholic acid
15
Similarly, ALGS is a hereditary disorder that results in the
16
Both conditions lead to
385
https://t.me/med1917
Chapter 17. Odevixibat (Bylvay)
(11) along with a range of other components including cholesterol, bilirubin, and
17
phospholipids.
Amongst these, bile acids make up roughly 80% of the total bile
composition and play a critical role in emulsifying and breaking down fats and fatsoluble vitamins for digestion.18
During the digestive process, bile is secreted from liver cells and released from
the liver through a series of bile ducts to perform its job as a digestive aid and detergent
in the GI tract. Upon reaching the ileum of the small intestine, the digested nutrients are
absorbed into the hepatic portal vein and filtered through the liver to enter systemic
circulation. Up to 95% of the bile acids initially secreted during digestion re-enter
enterohepatic circulation at this point via the IBAT.
sodium-dependent bile acid transport (ASBT), is a cotransporter glycoprotein. It can
recognize cholesterol derived bile-acids for transport into the portal vein to be recycled in
the liver for later digestive cycles.
Any dysfunction affecting enterohepatic bile flow can have serious long-term
health effects for patients. As both PFIC and ALGS are genetic conditions, they are
present at birth and often necessitate rapid diagnosis and treatment of the resulting liver
diseases.
19
IBAT, also known as the apical
18
386
https://t.me/med1917
Chemistry and Pharmacology of Drug Discovery
2.2. Genetic Disorders Aecting Bile Acid Homeostasis
The prevalence of genetically inherited disorders such as PFIC and ALGS are quite rare.
PFIC is estimated to occur only 1 in 50,000 to 100,000 births while ALGS is found in 1
out of 70,000 to 100,000 births. While both disorders are hereditary, PFIC is autosomal
recessive, requiring the mutant copy of the appropriate gene to be passed down from both
parents simultaneously for a chance the child develops PFIC.
is autosomal dominant and only requires a single copy of the mutant gene to be passed
21
from parent to child to have potential affect.
The genetic mutations associated with PFIC occur on the ATP8B1, ABCB11,
ABCB4, and Myo5B genes along with loss of function of the TJP2 and FXR proteins.
The ATP8B1 gene codes for the protein responsible for helping bile acids cross cell
membranes so that they can be released from liver cells. The ABCB11 gene encodes
information for the bile salt export pump which also assists in bile acid export out of the
intracellular matrix. The ABCB4 gene is responsible for a protein that enables
phospholipid binding of bile acids to help carry them in the extracellular matrix.
Mutations of these three genes are responsible for PFIC types 1, 2, and 3, respectively.
Also, loss of function of the Tight Junction Protein 2 (TJP2), Farnesoid X Receptor
(FXR), and genetic mutation of the Myo5B gene are associated with the newer PFIC
types 4, 5, and 6.
In the case of ALGS, the culprit is loss of function in the NOTCH signaling
pathway due to mutation of the JAG1 gene in most cases, or a small portion of cases
21
resulting from NOTCH2 gene mutation.
Mutation of the JAG1 gene either results in the
production of an abnormally short Jagged-1 protein that does not properly span the
transmembrane region of the cell or interferes with transport of the protein to the cell
membrane. In either case, loss of function of the Jagged-1 protein affects intercellular
communication via the highly conserved NOTCH signaling pathway responsible for
development of functioning bile ducts and proper cardiac function.
20
ALGS on the other hand
23
22
2.3. Structure and Function of the Ileal Bile Acid
Transporter
The human ileal bile acid transporter is a sodium-dependent 48-kDa glycoprotein
consisting of 348 amino acids that is encoded by the SLC10A2 gene. It is primarily
expressed on the apical surface of intestinal ileal enterocytes along with lesser expression
in renal tubule cells and the lining of biliary cholangiocytes. While the exact structure of
the human ileal bile acid transporter has not been fully elucidated, it is believed to
express seven transmembrane topologies, similar to other bile acid transporters like
24
NTCP.
bile acids conjugated to taurine or glycine from the intestines to the liver. IBAT functions
as a cotransporter which utilizes a sodium gradient to transport bile acids across the
As mentioned previously, its main purpose is the reabsorption of bile acids and
387
https://t.me/med1917
Chapter 17. Odevixibat (Bylvay)
cellular membrane.25 For every equivalent of bile acid transported, two equivalents of
sodium ions transport in the same direction.
Photo affinity labeling and enzymatic digestion studies have helped discern that
the substrate binding domain of the human IBAT likely lies in the seventh
transmembrane helix and C-terminus 56 through 67th amino acids. While heavily
debated, computational models for IBAT inhibitors tend to fall into the regime of
suggesting a hydrophobic core with hydrogen-bond acceptor and potentially hydrogenbond donor characteristics that extend deeper into the substrate binding pocket.
26, 27
Work on the structures of bacterial homologs of IBAT in Yersinia frederiksenii
and Neisseria meningitidis has further unveiled some of the mechanisms of the
25
transporter.
Each of the bacterial homologs host a ten-transmembrane helical structure
instead of the seven helices in humans. In bacterial homologs, TM helices 3–5 and 8–10
form the sodium-binding core motif of the transporter which can accept two sodium ions
largely coordinated by adjacent carbonyl backbone oxygen atoms. TM helices 1, 2, 6, and
7 form separate V-shaped motifs, which together with the adjacent core transmembrane
helices form the hydrophobic bile acid binding pocket (Figure
1).
The core motif shuttles two sodium ions from the intestinal lumen through the
enterocyte’s apical membrane through a sequence of oxygen and nitrogen atom chelation.
At the same time, bile acids fit into the substrate-binding cavity between the core and Vshaped motifs to be transported through the apical membrane as well. The bile acid then
Figure 1. Function of human ileal bile acid transporter (IBAT).
Соседние файлы в папке Библиотека им академика М.И. Перельмана