Somatostatin type 2 (SST2) receptor

Acromegaly is a hormonal disorder associated with excessive secretion of growth hormone (GH) and subsequent increase in the production of insulin-like growth factor I (IGF-I). Similar to the natural hormone somatostatin, paltusotine suppresses GH and IGF-1 secretion. Paltusotine exerts its pharmacological activity via selective agonism (>4000-fold) at somatostatin receptor 2 (SSTR2) and exhibits little or no affinity for other SST receptor subtypes. Paltusotine inhibited cyclic adenosine monophosphate accumulation via human SSTR2 activation with an average drug (agonist) concentration that results in half-maximal response (EC50) of 0.25 nM.

Paltusotine, a somatostatin receptor agonist, reduces IGF-1 levels in acromegaly patients in a dose-dependent manner across the 20 to 60 mg therapeutic dose range. Paltusotine may inhibit gallbladder contractility and decrease bile secretion, potentially leading to gallbladder stones or sludge. Paltusotine can also cause changes in glucose metabolism, potentially resulting in hyperglycemia or, less commonly, hypoglycemia. Somatostatin analogs, including paltusotine, may suppress thyroid-stimulating hormone secretion, potentially leading to hypothyroidism. Additionally, they can inhibit pancreatic enzyme and bile acid secretion, potentially causing malabsorption of dietary fats and steatorrhea. Decreased vitamin B12 levels have also been observed.

Absorption
In healthy subjects, pertuzumab exposure increased proportionally with increasing dose, ranging from 20 mg (lowest approved recommended dose) to 120 mg (twice the highest approved recommended dose). In patients with acromegaly, a significant dose-proportional increase in mean steady-state trough concentration was also observed with a once-daily dose of 60 mg. Steady-state exposure of pertuzumab is reached within one week after once-daily administration. The geometric mean absolute bioavailability of 20 mg pertuzumab as an oral solution is 69%, with little inter-individual variability. The median time to reach maximum plasma concentration (Tmax) after oral administration of pertuzumab is 1 to 4 hours, regardless of the duration of fasting. Food decreases the drug's AUC and Cmax.
Excretion
The primary route of excretion after oral administration of radiolabeled pertuzumab is fecal excretion, with total radioactive recoveries observed in feces (90%) and urine (3.9%). Unmetabolized pertuzumab is the main component of excrement.
Volume of Distribution
The volume of distribution (Vz) of pertuzumab is 220 L.
Clearance
The geometric mean (geometric coefficient of variation %CV) of the apparent oral clearance (CL/F) after a single oral dose of 20 mg pertuzumab is 8.4 (27.1) L/h.
Protein Binding
Pertuzumab has a high plasma protein binding rate (99%).
Metabolism/Metabolites
Pertuzumab is primarily metabolized in the liver. The primary metabolic pathway is glucuronidation, mainly catalyzed by UGT1A1 and UGT1A9 enzymes. The secondary pathway is oxidation, mainly catalyzed by CYP3A4/5, with less catalytic activity from CYP2D6. Four metabolites (M632/1, M472/1, M648/1, and M676/1) have been identified, with their main metabolic pathways being glucuronidation, monooxidation, and N-carbamoylglucuronidation.
Biological Half-Life
After reaching maximum concentration, the concentration of pertuxotine decreases, with an apparent terminal half-life of 28 hours.

Safety Information
Palsonify increases the risk of gallstones, hyperglycemia, hypoglycemia, bradycardia, thyroid dysfunction, steatorrhea, malabsorption of dietary fat, and changes in vitamin B12 levels. The most common side effects include diarrhea, abdominal pain, nausea, decreased appetite, bradycardia, hyperglycemia, and gastroenteritis.
Dosage and Administration
The recommended starting dose is 40 mg orally once daily with water on an empty stomach, at least 6 hours after a meal (i.e., after an overnight fast) and at least 1 hour before the next meal. During initial treatment, the dose of palsonify may be temporarily reduced to 20 mg once daily if necessary, depending on tolerance. Once adverse reactions subside, patients should resume the dose of 40 mg palsonify once daily. After 2 to 4 weeks of taking palsonify 40 mg once daily, patients may be advised to increase the dose to 60 mg once daily, depending on their IGF-1 levels.

[1]. Identification of a dose range for once daily oral paltusotine in patients with acromegaly that maintains IGF-1 levels when switching from long-acting somatostatin receptor ligand therapy. Endocrine Abstracts (2021) 73 OC15.4.

[2]. Pharmacokinetics and Safety of an Improved Oral Formulation of Paltusotine, a Selective, Non-Peptide Somatostatin Receptor 2 (SST2) Agonist for the Treatment of Acromegaly. Journal of the Endocrine Society, Volume 5, Issue Supplement_1, April-May 2021.

[3]. Discovery of Paltusotine (CRN00808), a Potent, Selective, and Orally Bioavailable Non-peptide SST2 Agonist. ACS Med Chem Lett. 2022 Dec 10;14(1):66-74.

This approval is based on data from two pivotal Phase 3 clinical trials, PATHFNDR-1 and PATHFNDR-2. These trials evaluated the safety and efficacy of PALSONIFY in treatment-naïve and therapy-naïve adult patients with acromegaly. In both trials, PALSONIFY demonstrated rapid onset of action, reliable biochemical control, and sustained efficacy. Participants also reported significant reductions in acromegaly-related signs and symptoms, assessed using an Acromegaly Symptom Diary (ASD). The ASD is an FDA-approved patient-reported outcome tool designed to record symptoms of concern to patients with acromegaly. These symptoms include headache, joint pain, sweating, fatigue, weakness, swelling, and/or numbness/tingling. PALSONIFY was generally well-tolerated, and no serious adverse events were reported in the randomized controlled portion of the trials. At this year's Endocrine Society Annual Meeting (ENDO 2025), long-term results from the open-label extension (OLE) phase of two trials were presented, further confirming that PALSONIFY can sustainably control IGF-1 levels, continuously improve patients' symptom burden, and has a good safety profile. 91% of patients in the PATHFNDR-1 trial and 97% of patients who completed the PATHFNDR-2 trial participated in the OLE phase. “The PATHFNDR clinical development program sets a new benchmark for acromegaly treatment, demonstrating that Palsonify effectively controls biochemical indicators and symptoms, regardless of the underlying disease severity,” said Dr. Shlomo Melmed, Executive Vice President of Medical and Health Sciences and Dean of the School of Medicine at Cedars-Sinai Medical Center. “The approval of Palsonify is a significant advancement for our patients, as there is a pressing need for an easily administered, safe, effective, rapid-onset, and durable treatment option to continuously control acromegaly.” Jill Sisco, Chair of the Acromegaly Community, stated, “Past treatments for acromegaly patients have meant cumbersome injections, recurring symptom flare-ups, and lifestyle sacrifices to maintain treatment. Our community prioritizes continuous disease control, not being controlled by the disease. This philosophy led us to collaborate with the FDA and conduct patient-centered external drug development meetings. The advent of this new therapy demonstrates that we are making our voice heard in shaping the next generation of acromegaly treatments.”

C27H24CL2F2N4O

529.41

528.12952

C, 61.26; H, 4.57; Cl, 13.39; F, 7.18; N, 10.58; O, 3.02

2172875-40-8

2172870-89-0; 2361216-83-1 (HCl); 2172875-40-8 (2HCl)

139299823

Typically exists as solids at room temperature

4

7

3

36

727

0

FC1C=C(C=C(C=1)C1=CN=C2C=CC(C3C=CC=C(C#N)C=3O)=CC2=C1N1CCC(CC1)N)F

GVTGYFQUBMBIAE-UHFFFAOYSA-N

InChI=1S/C27H22F2N4O.2ClH/c28-19-10-18(11-20(29)13-19)24-15-32-25-5-4-16(22-3-1-2-17(14-30)27(22)34)12-23(25)26(24)33-8-6-21(31)7-9-33;;/h1-5,10-13,15,21,34H,6-9,31H2;2*1H

3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-hydroxybenzonitrile;dihydrochloride

CRN00808 dihydrochloride; Paltusotine di-hydrochloride; FZT5Z83JNS; UNII-FZT5Z83JNS; 2361216-83-1; Benzonitrile, 3-(4-(4-amino-1-piperidinyl)-3-(3,5-difluorophenyl)-6-quinolinyl)-2-hydroxy-, hydrochloride (1:1); 2172875-40-8; Paltusotine dihydrochloride; 3-(4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dihydrochloride; Paltusotine (hydrochloride);

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)