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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5613_Библиотеки_им_академика_М_И_Перельмана
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Chemistry and Pharmacology of Drug Discovery
2.3. Bremelanotide
Palatin Technologies developed BMT (also known as PT-141, 1). After the Phase III
trials, Palatin Technologies partnered with AMAG Pharmaceuticals to complete the
development and commercialization further.
BMT (1) was originally developed as a potential sunless tanning agent and then
was discovered to cause sexual arousal. Therefore, it was investigated for the treatment of
male and female sexual dysfunction and turned into the treatment of premenopausal
3, 16, 17
women with HSDD.
The BMT (1) mechanism of action for treating male sexual
dysfunction is better understood. BMT (1) nonselectively activates several MCR
subtypes. In males, it primarily acts on MC3R and MC4R to help treat erectile
dysfunction. The stimulation of the MCRs, in general, causes a local increase of nitric
oxide in the penis and leads to vasodilation and penile erection (Figure 2).
In females who suffer from HSDD, it is considered that an imbalance of various
neurotransmitters causes abnormal sexual responses. Amongst the neurotransmitters,
dopamine (5) and melanocortin stimulate attention and desire, while norepinephrine (6)
and oxytocin (7) stimulate sexual arousal.16 BMT (1) administration acts primarily on the
presynaptic MC4R. It stimulates the release of dopamine (5) to portions of the nucleus
accumbens, mPOA, verbal tegmental area, arcuate nucleus, and the medial and
basolateral amygdala. These brain areas regulate the motivational, arousal, and appetitive
aspects of sexual behavior (Figure 1).
18, 19
15
Figure 2. BMT (1), mechanism of action. Source: Adapted from Clayton et a l.17
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Chapter 16. Bremelanoide (Vyleesi)
3. Structure–Activity Relationship (SAR)
3.1. Structure–Activity Relationship of Bremelanotide
BMT (1) is a synthetic, cyclic heptapeptide with a free acid at the carboxyl terminus and
an acetylated amino group at the amino terminus.
chains of Asp2 and Lys7 to form the lactam analog of α-MSH (12). BMT (1) sequence is
Ac-Nle-cyclo-(Asp-His-DPhe-Arg-Trp-Lys)-OH.
The des-α-MSH (16) peptide is derived from the N-terminal 13 residues of
14
ACTH (11).
and the C-terminal carboxyamidation (Figure 3). The N-terminal acetylation increases
the stability of α-MSH (12) compared to des-α-MSH (16). The plasma half-life
MSH (12) is 20–25 minutes in humans.
sub-nanomolar to nanomolar potencies to MCRs.
Both termini of α-MSH (12) are modified, with the N-terminal acetylation
20
The full-length peptide possesses nonselective
The cyclization is between the side
16
of α-
Figure 3. SAR of MCRs agonists
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Chemistry and Pharmacology of Drug Discovery
Since the sequence of α-MSH (12) was reported in 1957, this peptide has been
subjected to numerous SAR studies, including the sequence’s amino acid truncation and
alanine scan.
21
As indicated in Section 2.2, the natural agonist ligands all have the
invariant sequence His-Phe-Arg-Trp. It is the pharmacophore of the endogenous
melanocortin ligands. Except that, Met4 and Glu5 also affect functional activity.
NDP-MSH (MT-I, 17) is a synthetic α-MSH analog.22 Two amino acids, Met4
and Phe7, were substituted in α-MSH (12) to yield NDP-MSH (17). Methionine was
reported to be prone to oxidation when attempting to radiolabel α- or β-MSH. It was
replaced with norleucine and increased the potency relative to α-MSH. The Phe7 to
DPhe7 substitution was explored due to the observation that heat-alkali treatment of αMSH (12) enhanced activity, and the Phe7 position was a major site of racemization. The
DPhe-containing diastereoisomers (Figure 3) were at least an order of magnitude more
potent than the L-Phe analogs. In 2024, NDP-MSH (17) was approved in the European
23
Union as a treatment for adult erythropoietic protoporphyria.
MT-II (18) is also a synthetic analog of α-MSH and MCR agonist.
24, 25
MT-II
(18) is shorter than NDP-MSH (17)/α-MSH (12) after the truncation of three residues
from both the N- and C-termini. It was cyclized through a lactam bridge between Asp5
and Lys10, maintaining the His-DPhe-Arg-Trp active tetrapeptide sequence of NDP-
MSH (Figure 3). The rationale design of the cyclization site was based on the hypothesis
that there is a salt bridge between the Glu5 and Lys11 of α-MSH (12)/NDP-MSH (17)
based upon NMR and computer modeling. In addition to the truncation and cyclization of
MT-II (18), Glu5 and Gly10 were substituted with Asp5 and Lys10. MT-II (18) is still a
K
potent, nonselective melanocortin ligand with agonist activity;
values are 0.67, 6.6,
i
34, and 46 nM for MC1, MC4, MC3, and MC5 receptors.
Competitive Technologies, a technology transfer company operating on behalf
of the University of Arizona, licensed MT-II to Palatin Technologies as a sexual
dysfunction agent.26 Palatin ceased MT-II development (18) in 2000 and synthesized,
patented, and began to develop
differs in the C-terminus carboxy group where MT-II (18) has an amide.
BMT (1). It is a likely metabolite of MT-II (18) that
27
4. Pharmacokinetics and Drug Metabolism
After subcutaneous administration of BMT (1), its maximal levels occur after about 1 h,
with a range of 0.5 to 1.0 h. And BMT (1) has 100% bioavailability with a subcutaneous
injection. Its maximum plasma concentration reaches 72.8 ng/mL, and AUC is
276 h*ng/mL. Renal and hepatic impairment causes an increase in BMT's AUC. BMT’s
C
level reaches its plateau after a 7.5 mg dose administration. Its plasma protein
max
binding is 21%. BMT (1) is metabolized via hydrolysis of its peptide bonds. The
elimination half-life of BMT is 2.7 h, with a range of 1.9 to 4.0 h. BMT (1) has a mean
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Chapter 16. Bremelanoide (Vyleesi)
clearance of 6.5 ± 1.0 L/h. It is excreted 64.8% in urine and 22.8% in feces. BMT (1)
decreases gastric emptying and has been shown to reduce the rate and extent of
absorption of other orally administered drugs, particularly indomethacin (19) and
3, 28
naltrexone (20).
5. Efficacy and Safety
In preclinical studies, PT-141 (1) effect on cAMP accumulation in cells expressing the
human MC4R was measured.
16
PT-141 (1) inhibits
125
I-NDP-α-MSH binding to human
MC4R and MC3R. PT-141 (1) shows a higher affinity for MC4R than it does for MC3R.
PT-141 (1), as an MC4R agonist for the treatment of sexual dysfunction, was
administrated to rats with different routes. It results in a significant increase in the
number of erections. Direct injection into the lateral verntricle was eretogenic at doses
100- to 1000-fold lower than those required when given systemically.
In a placebo-controlled feasibility study, eighteen premenopausal women with a
primary diagnosis of female sexual arousal disorder were randomly assigned to receive a
single intranasal dose of 20 mg BMT (1).29 More women reported moderate or high
sexual desire following BMT (1) treatment, and a trend toward more positive responses
regarding feelings of genital arousal occurred. The initial clinical evidence of potential
BMT (1) benefit in female patients with impaired sexual arousal.
To evaluate the safety and tolerability of BMT (1), a phase I randomized double-
blind study assessed the administration of BMT (1) in conjunction with ethanol to
30
analyze pharmacokinetic interactions.
There were also no clinically significant changes
in blood pressure and no noticeable pharmacokinetic interactions with BMT (1)
administration alongside ethanol.
The phase IIB, placebo-controlled trial (NCT01382719) of BMT (1) was
conducted in a well-characterized population of premenopausal women with HSDD,
31
FSAD, or both to explore its safety and efficacy.
Subcutaneous doses of 0.75, 1.25, and
1.75 mg were selected. Self-administered subcutaneous BMT (1), taken as needed for up
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Chemistry and Pharmacology of Drug Discovery
to 12 weeks, and indicated dose-responsive improvements in desire, arousal, and
associated distress, as well as increases in the number of satisfying sexual events
compared with placebo. Effective dosing with 1.25 and 1.75 mg was established.
In two identical phase III, placebo-controlled trials (NCT02333071 and
NCT02338960) evaluated the safety and efficacy of BMT 1.75 mg administered
32
subcutaneously as needed in premenopausal women with HSDD.
Both studies indicated
that BMT significantly improved sexual desire and related distress in premenopausal
women with HSDD.
The phase I study results indicated that single doses of up to 10 mg (healthy
male subjects) and 6 mg (erectile dysfunction patients) of BMT (1) were safely
33
administered and well tolerated.
with mild to moderate renal and hepatic impairment.
No dosing adjustments are recommended for patients
3
The most commonly reported side
effects are flushing, headaches, nausea, and skin irritation. Most events were reported to
31, 32, 34
be mild (31%) to moderate (40%) in intensity and transient.
BMT (1) can significantly decrease the absorption of oral naltrexone (20), and
its concomitant use is not recommended. Intramuscular naltrexone (20) can be an
alternative for this subset of patients.3
6. Synthesis
BMT (1) is synthesized using the standard solid-phase peptide synthesis (SPPS) method
35–38
and supplied in acetate salt.
In the patent of Palatin Technologies, they reported the linear peptide synthesis
using SPPS with Fmoc chemistry. The patent indicated that the lysine side chain
protecting group can be Adpoc, Aloc, and Mtt. The aspartic acid side chain was protected
with an allyl group.
As an example, Fmoc-Lys(Aloc)-OH was coupled to the resin (21) to yield the
first amino acid loaded resin (22). The resin (21) was not specified in the patent. After
linear peptide assembly (23), the Lys and Asp side chain deprotected peptidyl resin (24)
was suspended in a suitable solvent (DMF, DCM, or NMP), an appropriate coupling
reagent (TBTU, TATU, TPTU, or DCC/HOBt) was added, and coupling reaction was
initiated using a suitable base (DIPEA or NMM) for cyclization. Then, the cyclized
peptidyl resin (25) was washed, and the peptide was cleaved from the resin using
trifluoroacetic acid (TFA) in the presence of water and ethanedithiol (EDT) (Scheme 1).
The crude of the final product (1) was precipitated with cold ether and collected
by filtration. Final purification was done using reversed-phase HPLC with a C18 column.
The purified peptide was converted to acetate salt with an ion-exchange column.
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Chapter 16. Bremelanoide (Vyleesi)
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Chemistry and Pharmacology of Drug Discovery
Scheme 1. Solid phase peptide synthesis of BMT (1)
In another patent, due to the concern of aspartimide formation during aspartic
35, 38
acid coupling step, a different synthesis strategy is adopted.
The carrier resin is Fmoc-Linker-AM resin (Scheme 2). The linker, 4hydroxybenzoic acid (HMBA), was coupled to the AM-resin (26) using conventional
condensation conditions with DIC and HOBt, furnishing modified HMBA-Rink-Amide-
AM-resin (27, Scheme 2).
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Scheme 2. HMBA-Rink-Amide-AM-resin preparation
The first amino acid, Fmoc-Lys(ivDde)-OH, is loaded to the HMBA-RinkAmide-AM-resin (27) through esterification to give 28 (Scheme
protecting group was deprotected with 20% piperidine/DMF solution to give 29. The
coupling of amino acids and Fmoc deprotection were continuously repeated to give 30.
The SPPS does not continue with aspartic acid coupling in the next step due to the
concern of aspartimide formation. Therefore, the ivDde protection group was removed on
resin using hydrazine monohydrate to yield 31. Coupling of Ac-Nle-Asp-OtBu (33) to 32
generates final linear peptidyl resin 34. The peptide was cleavage from the resin using
TFA cocktail (TFA:PhSMe:Phenol:EDT =
DMF:DCM = 2.5:1 using PyBop as condensation reagent. The protecting group of Ctermini COOH was hydrolyzed to get the final crude product of BMT (1). Final
purification was done as described above.
Chapter 16. Bremelanoide (Vyleesi)
3). Then N-Fmoc
90:5:2:3). The crude peptide was cyclized in
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Chemistry and Pharmacology of Drug Discovery
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Scheme 3. Synthesis of BMT (1)
Chapter 16. Bremelanoide (Vyleesi)
7. Summary
HSDD is a multifaceted disorder involving biological, psychological, and
pharmacological influences.
private nature of the condition, making it difficult for patients to discuss with physicians.
Female sexual dysfunction has not been studied as extensively as male sexual
dysfunction.
HSDD. However,
for
the data reporting and measurement practices were incomplete and lacked transparency.
Therefore, the drug is generally not useful. The debate on BMT (1) benefit to the patient
and the unknown exact mechanism of action in improving female HSDD indicate that
female HSDD treatment is still an unmet medical need.
FDA approval of Vyleesi (1) provides women with another treatment option
It often goes underdiagnosed and undertreated due to the
Spielmans reanalyzed phase III BMT (1) trials and suggested that
References
1. (a) Clayton, A.; Kingsberg, S.; Goldstein, I. Evaluation and
management of hypoactive sexual desire disorder. J. Sex. Med. 2017, 6,
59–74. (b) Goldstein, I.; Noel, K.; Clayton, A. Hypoactive sexual desire
disorder: International Society for the Study of Women’s Sexual Health
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