Treatment Outcomes of PED for Unruptured Aneurysms of Internal Carotid Artery: Comparison of PED-Flex and PED-Shield.

There is a lack of data regarding the safety and effectiveness of implanting the Pipeline Embolization Device with Shield technology (PED-Shield) compared with the previous generation of Pipeline (PED-Flex). This retrospective single-center study aimed to compare treatment outcomes between the PED-Shield and PED-Flex for treating unruptured internal carotid artery aneurysms. The PED-Flex was used in 62 procedures (67 aneurysms, 59 patients) and the PED-Shield in 53 procedures (59 aneurysms, 58 patients). The mean aneurysm diameter was significantly lower in the PED-Shield group than in the PED-Flex group (11.9 ± 7.0 mm vs. 15.2 ± 6.9 mm, p < 0.001). At the 12-month follow-up, the complete angiographic occlusion rate was 72.1% and 72.3% in the PED-Flex and PED-Shield groups, respectively (p = 0.9808). Limited to aneurysms larger than 10 mm, 70.6% and 68.0%, respectively (p = 0.8175). The incidence of more than three high signal intensity areas on diffusion-weighted imaging after treatment was significantly lower in the PED-Shield group than in the PED-Flex group (27.7% vs. 67.7%; p < 0.001). Limited to aneurysms larger than 10 mm, 41.1% and 69.6%, respectively (p < 0.0117). Symptomatic ischemic complications occurred within 30 days of four PED-Flex procedures (6.5%) and one PED-Shield procedure (2.0%) (p = 0.2315). Limited to aneurysms larger than 10 mm, 1.8% and 3.2%, respectively (p = 0.6677). The incidence of mRS score worsening at 6 months was 3.2% and 1.9% in the PED-Flex and PED-Shield groups, respectively (p = 0.6534). The PED-Shield can achieve outcomes equivalent to or better than the PED-Flex. Further large-scale studies are warranted to confirm our findings.

Extracranial internal carotid artery-dissecting aneurysm having a re-entry tear and causing lower cranial nerve palsies treated with flow-diverting stent: A case report.

Background: Extracranial internal carotid artery (ICA)-dissecting aneurysms (DAs) rarely cause re-entry tears and lower cranial nerve palsies. The therapeutic strategies for these pathologies are not well established. This report presents a case of an extracranial ICA -DA with a re-entry tear that caused lower cranial nerve palsy. Case Description: A 60-year-old man presented with left neck pain, hoarseness, and dysphagia. Physical examination and laryngoscopy determined palsies of the left cranial nerves IX, X, and XII. Digital subtraction angiography (DSA) revealed a DA in the left extracranial ICA, and three-dimensional DSA showed entry and re-entry tears in the intimal flap. Flow-diverting stents (FDSs) were placed on the lesion that covered the entry and re-entry tears because the symptoms did not improve after five weeks of conservative treatment. A post-procedural angiogram indicated flow stagnation in the DA. Symptoms improved remarkably immediately after the procedure, and the aneurysm was almost completely occluded six months later. Conclusion: Herein, an extracranial ICA -DA with a re-entry tear that caused lower cranial nerve palsy did not improve after five weeks of conservative treatment. FDS placement promptly resolved the aneurysm and symptoms. Thus, FDS placement may be an effective treatment option for extracranial ICA-DAs with re-entry tears or lower cranial nerve palsies.

Fungal symptomatic intracranial aneurysm treated with a flow diverting stent: A case report.

Background: Intracranial infectious aneurysms (IIAs) are very rare, and fungal aneurysms are infrequently reported. We report a case of an unruptured IIA caused by fungal rhinosinusitis and treated with a flow-diverting stent. Case Description: An 81-year-old woman visited the ophthalmology department with impaired eye movement and ptosis and was placed under follow-up. A week later, she also developed a headache; magnetic resonance angiography revealed an aneurysm measuring 2 mm in the C4 portion of the right internal carotid artery. A 3-week follow-up with contrast-enhanced magnetic resonance imaging showed an increase in its size to 10 mm, and a contrast lesion was observed surrounding the right cavernous sinus. The patient started treatment with voriconazole and steroids on the same day. Ten weeks later, despite improvements in inflammation, the size of the aneurysm was unchanged; we, therefore, treated the aneurysm with a flow-diverting stent. Oculomotor nerve palsy improved, and the patient was discharged to a rehabilitation hospital 28 days after the placement, with a modified Rankin Scale of 4. A 1-year follow-up angiogram showed a partial decrease in the size of the aneurysm, with an O'Kelly-Marotta grading scale of B3. Conclusion: IIAs grow rapidly, and the risk of rupture is high due to the weakening of the aneurysmal wall. To reduce the risks of rupture and recurrence after treatment, the infection should be treated before inserting a flow-diverting stent. Flow-diverting stent placement may be an effective treatment for IIA once the original infection has been cured.

Predictors of Middle Meningeal Artery-Related Vascular Diseases Associated with Blunt Head Trauma.

OBJECTIVE: Traumatic middle meningeal artery (MMA)-middle meningeal vein (MMV) fistula (MMA-MMV fistula) and MMA pseudoaneurysm are the 2 main MMA-related vascular diseases occurring after blunt head trauma. These are rare but known causes of delayed intracranial hemorrhage. This study investigated predictors that may aid in the diagnosis of these diseases. METHODS: In our department, screening digital subtraction angiography (DSA) is performed for patients with blunt head trauma accompanied by intracranial hemorrhage and skull or facial bone fracture. This study included 87 patients who underwent screening DSA without craniotomy from January 2019 to June 2023. The patients' clinical characteristics were retrospectively collected from the database. Statistical analysis was performed to examine the associations of various evaluation items with MMA-related vascular diseases. RESULTS: The first DSA examination revealed 34 MMA-MMV fistulas and 1 MMA pseudoaneurysm. The second follow-up DSA examination revealed 13 MMA-MMV fistulas and four MMA pseudoaneurysms. Temporal/parietal bone fracture (odds ratio, 5.33; P = 0.0005; 95% confidence interval, 1.95-14.60) was significantly associated with MMA-related vascular diseases. Endovascular treatments were performed in 9 patients. All procedures were successfully completed without complications; no delayed bleeding was observed. CONCLUSIONS: Temporal/parietal bone fracture in patients with blunt head trauma is a likely predictor of MMA-related vascular diseases. When initial head computed tomography reveals this pathology, we recommend careful imaging follow-up (e.g., DSA) and treatment as needed, while considering the possibility of MMA-related vascular diseases.

Observation of the Sign Reversal of the Magnetic Correlation in a Driven-Dissipative Fermi Gas in Double Wells.

We report the observation of the sign reversal of the magnetic correlation from antiferromagnetic to ferromagnetic in a dissipative Fermi gas in double wells, utilizing the dissipation caused by on-site two-body losses in a controlled manner. We systematically measure dynamics of the nearest-neighbor spin correlation in an isolated double-well optical lattice, as well as a crossover from an isolated double-well lattice to a one-dimensional uniform lattice. In a wide range of lattice configurations over an isolated double-well lattice, we observe a ferromagnetic spin correlation, which is consistent with a Dicke type of correlation expected in the long-time limit. This work demonstrates the control of quantum magnetism in open quantum systems with dissipation.

Staged treatment for ruptured wide-neck intracranial aneurysm with intentional partial coiling in the acute phase followed by definitive treatment.

Background: Evidence supports endovascular coiling for ruptured intracranial aneurysms (RIAs). However, in some cases, it is difficult to achieve complete occlusion by coiling, such as with wide-neck aneurysms. We report our experience with intentional staged RIA treatment using targeted endovascular coiling at the rupture point in the acute phase, followed by delayed stent-assisted coiling, flow diverter stenting, or surgical clipping. Methods: Consecutive patients with RIAs treated between April 2015 and June 2021 were retrospectively investigated. Clinical characteristics, treatment complications, and patient outcomes data were collected. Results: Among 108 RIAs treated in our hospital, 60 patients underwent initial coiling; 10 patients underwent staged treatment. The aneurysm locations were the anterior communicating artery (n = 5), internal carotid-posterior communicating artery (n = 3), internal carotid-paraclinoid (n = 1), and vertebral artery-posterior inferior cerebellar artery (n = 1). The mean ± standard deviation aneurysmal diameter was 9.6 ± 5.4 mm and the mean aspect ratio was 1.2 ± 0.7. As the second treatment to obliterate blood flow to the neck area, we performed five stent-assisted coiling, two flow-diverter stentings, and three surgical clippings. Only one minor perioperative complication occurred. The median duration between the first and second treatments was 18 days (range, 14- 42 days). Good clinical outcome (modified Rankin scale score 0-2) at 90 days was achieved in 5 (50%) cases. The median follow-up duration was 6.5 months (range, 3-35 months); no rerupture occurred. Conclusion: Intentional staged treatment with a short time interval for RIA was effective and feasible.

Stent infection and pseudoaneurysm formation after carotid artery stent treated by excision and in situ reconstruction with polytetrafluoroethylene graft: A case report.

BACKGROUND: Stent infection after carotid artery stenting (CAS) can be a life-threatening postoperative complication, but there is a paucity of data due to its exceedingly low frequency. We report a case of stent infection with pseudoaneurysm formation after CAS that was treated through replacing the infected stent and pseudoaneurysm with a polytetrafluoroethylene (PTFE) synthetic vessel graft. CASE DESCRIPTION: An 86-year-old man was treated for the right internal carotid artery with CAS in local hospital. One month after stenting, he suffered aspiration pneumonia and septicemia. Three months after stenting, swelling and tenderness of the right side of his neck appeared. His general condition deteriorated due to septicemia and he was unable to ingest anything by mouth as a result of decreasing levels of consciousness. He was transferred to our hospital. Computed tomography and digital subtraction angiography showed the presence of a pseudoaneurysm around the stent. The neck mass enlarged daily and surgical intervention was required to prevent closure of the airway. Stent and pseudoaneurysm resection and in situ reconstruction with a PTFE synthetic vessel graft were performed. The patient returned to his local hospital 36 days after surgery and had a modified Rankin Score of 5. CONCLUSION: Although the risk of reinfection is high due to the nature of artificial material, stent/pseudoaneurysm resection and in situ reconstruction with a PTFE synthetic vessel graft might be one of the best options for patients suffering stent infection after CAS. To the best of our knowledge, this is the first report of treatment using this material.

Isostearyl Mixed Anhydrides for the Preparation of N-Methylated Peptides Using C-Terminally Unprotected N-Methylamino Acids.

Sustainable and efficient manufacturing methods for N-methylated peptides remain underexplored despite growing interest in therapeutic N-methylated peptides within the pharmaceutical industry. A methodology for the coupling of C-terminally unprotected N-methylamino acids mediated by an isostearic acid halide (ISTAX) and silylating reagent has been developed. This approach allows for the coupling of a wide variety of amino acids and peptides in high yields under mild conditions without the need for a C-terminal deprotection step in the process of C-terminal elongation. These advantages make this a useful synthetic method for the production of peptide therapeutics and diagnostics containing N-methylamino acids.

A new class of pentapeptide KISS1 receptor agonists with hypothalamic-pituitary-gonadal axis activation.

The kisspeptin (Kp, Kp-54, metastin)/KISS1R system plays crucial roles in regulating the secretion of gonadotropin-releasing hormone. Continuous administration of nonapeptide Kp analogs caused plasma testosterone depletion, whereas bolus administration caused strong plasma testosterone elevation in male rats. To develop a new class of small peptide drugs, we focused on stepwise N-terminal truncation of Kp analogs and discovered potent pentapeptide analogs. Benzoyl-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (16) exhibited high agonist activity for KISS1R and excellent metabolic stability in rat serum. A single injection of a 4-pyridyl analog (19) at the N-terminus of 16 into male Sprague Dawley rats caused a robust increase in plasma luteinizing hormone levels, but unlike continuous administration of nonapeptide Kp analogs, continuous administration of 19 maintained moderate testosterone levels in rats. These results indicated that small peptide drugs can be successfully developed for treating sex hormone deficiency.

Antiobesity and emetic effects of a short-length peptide YY analog and its PEGylated and alkylated derivatives.

Neuropeptide Y2 receptor (Y2R) agonism is an important anorectic signal and a target of antiobesity drug discovery. Recently, we synthesized a short-length Y2R agonist, PYY-1119 (4-imidazolecarbonyl-[d-Hyp24,Iva25,Pya(4)26,Cha27,36,γMeLeu28,Lys30,Aib31]PYY(23-36), 1) as an antiobesity drug candidate. Compound 1 induced marked body weight loss in diet-induced obese (DIO) mice; however, 1 also induced severe vomiting in dogs at a lower dose than the minimum effective dose administered to DIO mice. The rapid absorption of 1 after subcutaneous administration caused the severe vomiting. Polyethylene glycol (PEG)- and alkyl-modified derivatives of 1 were synthesized to develop Y2R agonists with improved pharmacokinetic profiles, i.e., lower maximum plasma concentration (Cmax) and longer time at maximum concentration (Tmax). Compounds 5 and 10, modified with 20 kDa PEG at the N-terminus and eicosanedioic acid at the Lys30 side chain of 1, respectively, showed high Y2R binding affinity and induced significant body weight reduction upon once-daily administration to DIO mice. Compounds 5 and 10, with their relatively low Cmax and long Tmax, partially attenuated emesis in dogs compared with 1. These results indicate that optimization of pharmacokinetic properties of Y2R agonists is an effective strategy to alleviate emesis induced by Y2R agonism.

Differential effects of selective agonists of neuromedin U1 and U2 receptors in obese and diabetic mice.

BACKGROUND AND PURPOSE: Neuromedin U (NmU) may be a novel target for obesity treatment owing to its anorectic and energy expenditure enhancing effects. Although two receptors, NMU1 and NMU2, are both responsible for the NmU-mediated anti-obesity effects, the receptor agonist with the most appropriate profiles for treating obesity and diabetes in terms of efficacy and safety is as yet unknown. Thus, we developed and evaluated novel NMU1/2 receptor-selective agonists. EXPERIMENTAL APPROACH: Efficacy and safety were assessed in mice with diet-induced obesity (DIO) and those with leptin-deficient diabetes (ob/ob) through repeated peripheral administration of selective agonists to NMU1 (NMU-6102) and NMU2 (NMU-2084), along with non-selective NMU1/2 agonists (NMU-0002 and NMU-6014). We also performed immunohistochemistry for c-Fos protein expression in the brain to probe their mechanisms of action. KEY RESULTS: Although both non-selective NMU1/2 agonists and the NMU2-selective agonist had high efficacy compared with the NMU1-selective agonist, only the NMU2-selective agonist led to relatively low adverse effects, such as diarrhoea, in DIO mice. However, the non-selective NMU1/2 agonist and the NMU1-selective agonist, but not the NMU2-selective agonist, were effective in diabetic ob/ob mice. Mechanistically, NMU2-selective agonists preferentially activate pro-opiomelanocortin neurons in the hypothalamic arcuate nucleus but not in the paraventricular nucleus. CONCLUSIONS AND IMPLICATIONS: These results suggest that an NMU2 receptor-selective agonist may be a well-balanced drug for the treatment of obesity and that an NMU1 receptor-selective agonist may also be beneficial for treating obesity and diabetes once its side effects are minimized.

A potent neuromedin U receptor 2-selective alkylated peptide.

Neuromedin U (NMU) mediates various physiological functions via NMUR1 and NMUR2 receptors. NMUR2 has been considered a promising treatment option for diabetes and obesity. Although NMU-8, a shorter peptide, has potent agonist activity for both receptors, it is metabolically unstable. Therefore, NMU-8 analogs modified with long-chain alkyl moieties via a linker were synthesized. An octadecanoyl analog (17) with amino acid substitutions [αMePhe19, Nle21, and Arg(Me)24] and a linker [Tra-γGlu-PEG(2)] dramatically increased NMUR2 selectivity, with retention of high agonist activity. Subcutaneous administration of 17 induced anorectic activity in C57BL/6J mice. Owing to its high metabolic stability, 17 would be useful in clarifying the physiological role and therapeutic application of NMU.

Highly potent antiobesity effect of a short-length peptide YY analog in mice.

Continuous administration of a 14-amino acid peptide YY (PYY) analog, Ac-[d-Pro24,Pya(4)26,Cha27,36,Aib28,31,Lys30]PYY(23-36) (4), which has a high binding affinity and agonist activity for the neuropeptide Y2 receptor (Y2R), has previously shown an antiobesity effect in a 2-week diet-induced obesity (DIO) study in mice. However, there remained a possibility to obtain more potent analogs by further improving its pharmacokinetic profile. A combination of the N-terminal 4-imidazolecarbonyl moiety and three amino acid substitutions, trans-4-hydroxy-d-proline (d-Hyp)24, isovaline (Iva)25, and γ-methylleucine (γMeLeu)28, not only improved the binding affinity of the peptide for Y2R but also increased its anorectic activity in lean mice. In a 2-week DIO study in mice, continuous administration of 4-imidazolecarbonyl-[d-Hyp24,Iva25,Pya(4)26,Cha27,36,γMeLeu28,Lys30,Aib31]PYY(23-36) (31, PYY-1119) at a dose of 0.03mg/kg/day showed a highly potent antiobesity effect, with more than 10% body weight reduction.

Potent antiobesity effect of a short-length peptide YY-analogue continuously administered in mice.

The gastrointestinal peptide, peptide YY3-36 (PYY3-36) and its shorter peptide analogues have been reported to reduce appetite by activating the neuropeptide Y2 receptor (Y2R), which is associated with obesity and other metabolic diseases. A 14-amino acid PYY analogue, Ac-[d-Pro24,Cha27,28,36,Aib31]PYY(23-36) (3), showed high binding affinity and agonist activity for the Y2R, similar to that of PYY3-36, but had weak anorectic activity upon continuous administration in lean mice. Three amino acid substitutions [Pya(4)26, Aib28, Lys30], which contributed to the decreased hydrophobicity of 3, efficiently increased its anorectic activity. The compound containing these three amino acids, Ac-[d-Pro24,Pya(4)26,Cha27,36,Aib28,31,Lys30]PYY(23-36) (22), exerted more potent and durable food intake suppression than that by PYY3-36 in lean mice, as well as excellent Y2R agonist activity (EC50: 0.20nM) and good subcutaneous bioavailability (66.6%). The 11-day continuous administration of 22 at 1mg/kg/day successfully produced antiobese and antidiabetic effects, with more than 20% body weight loss in obese and Type 2 diabetes ob/ob model mice.

Antiobesity Effect of a Short-Length Peptide YY Analogue after Continuous Administration in Mice.

Gastrointestinal peptides such as peptide YY (PYY) can regulate appetite, which is relevant to the study of obesity. The intraperitoneal bolus administration of PYY3-36 and a 12-amino acid PYY analogue, benzoyl-[Cha27,28,36,Aib31]PYY25-36 (1), showed similar anorectic activity by activating the Y2 receptor (Y2R). However, food intake inhibition and body weight loss were not observed upon continuous subcutaneous administration of 1 with osmotic pumps in diet-induced obese (DIO) mice. N-Terminal elongation of 1, together with amino acid substitution at position 24, led to a hydrophilic 14-amino acid peptide, Ac-[d-Hyp24,Cha27,28,36,Aib31]PYY23-36 (18), that showed higher affinity and more potent agonist activity for Y2R and a robust anorectic activity with potency similar to that of PYY3-36. In addition, the continuous subcutaneous administration of 18 at 0.3 mg/(kg·day) induced significant body weight loss in DIO mice. These results suggest that a short-length PYY analogue can be a lead compound for antiobesity therapy in a sustained-release formulation.

A potent and selective natriuretic peptide receptor-3 blocker 11-mer peptide created by hybridization of musclin and atrial natriuretic peptide.

The natriuretic peptide (NP) system is a critical endocrine, autocrine, and paracrine system and has been investigated for potential use against cardiovascular and metabolic diseases. The clearance of NPs is regulated by the proteolysis of neutral endopeptidase (NEP) and by endocytosis via natriuretic peptide receptor-3 (NPR3). A linear NPR3-selective peptide, [Cha8]-ANP(7-16)-NH2 (1), showed potent binding affinity for NPR3 but poor predicted chemical stability due to its free thiol group. A 12-mer peptide (9) without a thiol group was designed by the hybridization of two NPR3-binding peptides: a linear ANP fragment peptide analog and musclin, a murine member of the bHLH family of transcription factors, possessed high binding affinity and strict selectivity for NPR3. To increase the proteolytic resistance of 9, amino acid substitutions at the cleavage sites led to hydroxyacetyl-[d-Phe5,d-Hyp7,Cha8,d-Ser9,Hyp11,Arg(Me)14]-ANP(5-15)-NHCH3 (23), showing high and selective binding affinity for NPR3 over NPR1 and excellent stability in mouse serum. Compound 23 increased intracellular cGMP concentrations in primary cultured adipocytes, and continuous administration induced substantial plasma cGMP elevation in mice, suggesting its potential to clarify the physiological role of NPR3 and its therapeutic application.

Potent Body Weight-Lowering Effect of a Neuromedin U Receptor 2-selective PEGylated Peptide.

Neuromedin U (NMU) is a neuropeptide that mediates a variety of physiological functions via its receptors, NMUR1 and NMUR2. Recently, there has been an increased focus on NMU as a promising treatment option for diabetes and obesity. A short form of NMU (NMU-8) has potent agonist activity for both receptors but is metabolically unstable. Therefore, we designed and synthesized NMU-8 analogues modified by polyethylene glycol (PEG; molecular weight, 20 kDa; PEG20k) via a linker. 3-(2-Naphthyl)alanine substitution at position 19 increased NMUR2 selectivity of NMU-8 analogues with retention of high agonist activity. Compound 37, an NMUR2-selective PEG20k analogue containing piperazin-1-ylacetyl linker, exhibited a potent body weight-lowering effect with concomitant inhibition of food intake in a dose-dependent manner (body weight loss of 12.4% at 30 nmol/kg) by once-daily repeated dosing for 2 weeks in mice with diet-induced obesity.

A PEGylated analog of short-length Neuromedin U with potent anorectic and anti-obesity effects.

Neuromedin U (NMU) is a neuropeptide known to regulate food intake and energy homeostasis that is widely distributed in the gastrointestinal tract, hypothalamus, and pituitary. A short form of NMU, porcine NMU-8 has potent agonist activity for the receptors NMUR1 and NMUR2; however, its short half-life precludes its effective use in vivo. To address this limitation, we designed and synthesized NMU-8 analogs modified by polyethylene glycol (PEG) with a molecular weight of 30kDa (PEG30k) via a variety of linkers (i.e., ω-amino- and ω-imino-carboxylic acid linker). Integrated evaluation of NMUR1 and NMUR2 binding affinities in vitro and anorectic activity in mice revealed that the introduction of a linker with a rigid ring group, e.g., 2-(piperazin-1-yl)acetic acid (PipAc), yielded a highly potent anorectic peptide, PEG30k-PipAc-NMU-8 (14), possessing improved receptor binding affinity. Subsequent optimization of the molecular weight of the PEG moiety led to the discovery of a PEG20k conjugate (15), which exhibited significant anti-obesity effect upon once-daily subcutaneous administration in diet-induced obese mice with 10% and 22% body weight loss at doses of 10 and 30nmol/kg, respectively. In addition, 15 reduced the weights of the liver and adipose tissue in a dose-dependent manner and improved the plasma biochemical parameters, e.g., insulin, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, and total cholesterol. Thus, our results suggest that 15 (NMU-0002), which showed potent and long-lasting biological profiles in vivo, represents a candidate peptide for investigating the central and peripheral actions of NMU and its potential for clinical use.

A Short-Length Peptide YY Analogue with Anorectic Effect in Mice.

Peripheral administration of PYY3-36, a fragment of peptide YY (PYY), has been reported to reduce food intake by activating the neuropeptide Y2 receptor (Y2R). An N-terminally truncated PYY analogue, benzoyl-[Ala26,Ile28,31]PYY(25-36) (1), showed a relatively potent agonist activity for Y2R but a weak anorectic activity by intraperitoneal administration (2000 nmol/kg) in lean mice because of its markedly poor biological stability in the mouse serum. Notably, two cyclohexylalanine (Cha) substitutions for Tyr residues at positions 27 and 36 (4) improved the stability in the mouse serum concomitant with enhanced anorectic activity. Further optimization at positions 27, 28, 30, and 31 revealed that 21, containing Cha28 and Aib31 residues, showed a more potent anorectic activity than PYY3-36 at a low dose of 300 nmol/kg. The minimum effective dose by intraperitoneal administration of 21 was 30 nmol/kg (ca. 52 µg/kg) in mice, suggesting the biologic potential of short-length PYY3-36 analogues with a potent anorectic effect.

Design and Synthesis of an Investigational Nonapeptide KISS1 Receptor (KISS1R) Agonist, Ac-d-Tyr-Hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (TAK-448), with Highly Potent Testosterone-Suppressive Activity and Excellent Water Solubility.

Metastin/kisspeptin is an endogenous ligand of KISS1 Receptor (KISS1R). Metastin and KISS1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacological activity to 1 but also excellent water solubility. Furthermore, 20 mg/mL aqueous solution of 24 did not show gel formation up to 5 days.