Naldemedine free base | CAS#916072-89-4 | μ-opioid receptor antagonist

MedKoo Cat#: 326729 | Name: Naldemedine

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Naldemedine (S 297995;) is a peripherally acting μ-opioid receptor antagonist (PAMORA) primarily developed to treat opioid-induced constipation (OIC) without affecting central analgesia. It exhibits high binding affinity to the human μ-opioid receptor with a Ki of 0.22 nM and also shows antagonistic activity at κ- and δ-opioid receptors with Ki values of 2.4 nM and 4.4 nM, respectively.

Chemical Structure

Naldemedine

CAS#916072-89-4 (free base)

Theoretical Analysis

MedKoo Cat#: 326729

Name: Naldemedine

CAS#: 916072-89-4 (free base)

Chemical Formula: C32H34N4O6

Exact Mass: 570.2478

Molecular Weight: 570.65

Elemental Analysis: C, 67.35; H, 6.01; N, 9.82; O, 16.82

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Related CAS #

1345728-04-2 (tosylate) 916072-89-4 (free base)

Synonym

S 297995; S-297995; S297995; S 297,995; S-297,995; S297,995; Naldemedine; Symproic;

IUPAC/Chemical Name

17-(cyclopropylmethyl)-6,7-didehydro-4,5alpha-epoxy-3,6,14-trihydroxy-N-(2-(3-phenyl- 1,2,4-oxadiazol-5-yl)propan-2-yl)morphinan-7-carboxamide

InChi Key

AXQACEQYCPKDMV-PFMBVUTNSA-N

InChi Code

InChI=1S/C32H34N4O6/c1-30(2,29-33-27(35-42-29)18-6-4-3-5-7-18)34-28(39)20-15-32(40)22-14-19-10-11-21(37)25-23(19)31(32,26(41-25)24(20)38)12-13-36(22)16-17-8-9-17/h3-7,10-11,17,22,26,37-38,40H,8-9,12-16H2,1-2H3,(H,34,39)/t22-,26-,31+,32-/m1/s1

SMILES Code

O=C(C1=C(O)[C@@H]2[C@]34C5=C(O2)C(O)=CC=C5C[C@@H](N(CC6CC6)CC4)[C@]3(O)C1)NC(C)(C7=NC(C8=CC=CC=C8)=NO7)C

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

In clinical studies, a once-daily oral dose of 0.2 mg significantly improved spontaneous bowel movement frequency in patients with chronic non-cancer pain receiving opioids, with response rates of ~47.6% versus 34.6% for placebo (p < 0.001). Naldemedine is metabolized by CYP3A and has a low ability to cross the blood-brain barrier due to its large polar surface area and interaction with P-glycoprotein, limiting central nervous system penetration and preserving opioid analgesia.

Product Data

Product Data

Instruction

View handling instruction

Biological target:

Naldemedine (S-297995) is an orally active μ-opioid receptor antagonist (PAMORA).

In vitro activity:

The binding affinity and antagonist activity of naldemedine against recombinant human μ-, δ-, and κ-opioid receptors were assayed in vitro. Naldemedine showed potent binding affinity and antagonist activities for recombinant human μ-, δ-, and κ-opioid receptors. Reference: Br J Cancer. 2022 Nov;127(8):1565-1574. https://pubmed.ncbi.nlm.nih.gov/30821019/

In vivo activity:

Therefore, this study used naldemedine, a peripherally acting MOR (μ-opioid receptor) antagonist, and MOR-knockout mice to investigate the involvement of peripheral MOR in tramadol-induced constipation using a small intestinal transit model. A single dose of tramadol (3-100 mg/kg, per os (p.o.)) inhibited small intestinal transit dose-dependently in rats. Naldemedine (0.01-10 mg/kg, p.o.) blocked the inhibition of small intestinal transit induced by tramadol (30 mg/kg, p.o.) in rats. The transition rate increased dose-dependently over the range of naldemedine 0.01-0.3 mg/kg, and complete recovery was observed at 0.3-10 m/kg. Reference: Biol Pharm Bull. 2021;44(11):1746-1751. https://pubmed.ncbi.nlm.nih.gov/34719650/

Preparing Stock Solutions

The following data is based on the product molecular weight 570.65 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Gondoh E, Hamada Y, Mori T, Iwazawa Y, Shinohara A, Narita M, Sato D, Tezuka H, Yamauchi T, Tsujimura M, Yoshida S, Tanaka K, Yamashita K, Akatori H, Higashiyama K, Arakawa K, Suda Y, Miyano K, Iseki M, Inada E, Kuzumaki N, Narita M. Possible mechanism for improving the endogenous immune system through the blockade of peripheral μ-opioid receptors by treatment with naldemedine. Br J Cancer. 2022 Nov;127(8):1565-1574. doi: 10.1038/s41416-022-01928-x. Epub 2022 Aug 9. PMID: 35945243; PMCID: PMC9553910. 2. Kanemasa T, Koike K, Arai T, Ono H, Horita N, Chiba H, Nakamura A, Morioka Y, Kihara T, Hasegawa M. Pharmacologic effects of naldemedine, a peripherally acting μ-opioid receptor antagonist, in in vitro and in vivo models of opioid-induced constipation. Neurogastroenterol Motil. 2019 May;31(5):e13563. doi: 10.1111/nmo.13563. Epub 2019 Feb 28. PMID: 30821019; PMCID: PMC6850587. 3. Yasufuku K, Koike K, Kobayashi M, Chiba H, Kitaura M, Takenouchi S, Hasegawa M, Morioka Y, Mishima H, Suzuki T, Fujita M. Involvement of the Peripheral μ-Opioid Receptor in Tramadol-Induced Constipation in Rodents. Biol Pharm Bull. 2021;44(11):1746-1751. doi: 10.1248/bpb.b21-00474. PMID: 34719650. 4. Kanemasa T, Matsuzaki T, Koike K, Hasegawa M, Suzuki T. Preventive effects of naldemedine, peripherally acting μ-opioid receptor antagonist, on morphine-induced nausea and vomiting in ferrets. Life Sci. 2020 Sep 15;257:118048. doi: 10.1016/j.lfs.2020.118048. Epub 2020 Jul 2. PMID: 32622946.

In vitro protocol:

In vivo protocol:

1. Yasufuku K, Koike K, Kobayashi M, Chiba H, Kitaura M, Takenouchi S, Hasegawa M, Morioka Y, Mishima H, Suzuki T, Fujita M. Involvement of the Peripheral μ-Opioid Receptor in Tramadol-Induced Constipation in Rodents. Biol Pharm Bull. 2021;44(11):1746-1751. doi: 10.1248/bpb.b21-00474. PMID: 34719650. 2. Kanemasa T, Matsuzaki T, Koike K, Hasegawa M, Suzuki T. Preventive effects of naldemedine, peripherally acting μ-opioid receptor antagonist, on morphine-induced nausea and vomiting in ferrets. Life Sci. 2020 Sep 15;257:118048. doi: 10.1016/j.lfs.2020.118048. Epub 2020 Jul 2. PMID: 32622946.

1: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Available from http://www.ncbi.nlm.nih.gov/books/NBK548373/ PubMed PMID: 31643694. 2: Ishii K, Yamashita H, Yamaguchi M, Komatsu Y, Ryu E, Morishita S, Matsuo K, Kamada M, Ikeda T, Ashizawa K, Hara T. Naldemedine-induced Opioid Withdrawal Syndrome in a Patient with Breast Cancer without Brain Metastasis: A Case Report. Intern Med. 2019 Sep 18. doi: 10.2169/internalmedicine.3098-19. [Epub ahead of print] PubMed PMID: 31534081. 3: Osaka I, Ishiki H, Yokota T, Tada Y, Sato H, Okamoto M, Satomi E. Safety and efficacy of naldemedine in cancer patients with opioid-induced constipation: a pooled, subgroup analysis of two randomised controlled studies. ESMO Open. 2019 Jul 31;4(4):e000527. doi: 10.1136/esmoopen-2019-000527. eCollection 2019. PubMed PMID: 31423335; PubMed Central PMCID: PMC6677965. 4: Blair HA. Naldemedine: A Review in Opioid-Induced Constipation. Drugs. 2019 Jul;79(11):1241-1247. doi: 10.1007/s40265-019-01160-7. Review. PubMed PMID: 31267482. 5: Sato J, Tanaka R, Ishikawa H, Suzuki T, Shino M. A preliminary study of the effect of naldemedine tosylate on opioid-induced nausea and vomiting. Support Care Cancer. 2019 Jun 11. doi: 10.1007/s00520-019-04884-0. [Epub ahead of print] PubMed PMID: 31183560. 6: Wild J, Yamada T, Arjona Ferreira JC, Hale M. Onset of action of naldemedine in the treatment of opioid-induced constipation in patients with chronic noncancer pain: results from 2 randomized, placebo-controlled, phase 3 trials. Pain. 2019 Oct;160(10):2358-2364. doi: 10.1097/j.pain.0000000000001629. PubMed PMID: 31145214; PubMed Central PMCID: PMC6756260. 7: Fukumura K, Yamada T, Yokota T, Kawasaki A. The Influence of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Naldemedine. Clin Pharmacol Drug Dev. 2019 Apr 12. doi: 10.1002/cpdd.690. [Epub ahead of print] PubMed PMID: 30977959. 8: Esmadi M, Ahmad D, Hewlett A. Efficacy of naldemedine for the treatment of opioid-induced constipation: A meta-analysis. J Gastrointestin Liver Dis. 2019 Mar;28(1):41-46. doi: 10.15403/jgld.2014.1121.281.any. PubMed PMID: 30851171. 9: Kanemasa T, Koike K, Arai T, Ono H, Horita N, Chiba H, Nakamura A, Morioka Y, Kihara T, Hasegawa M. Pharmacologic effects of naldemedine, a peripherally acting μ-opioid receptor antagonist, in in vitro and in vivo models of opioid-induced constipation. Neurogastroenterol Motil. 2019 May;31(5):e13563. doi: 10.1111/nmo.13563. Epub 2019 Feb 28. PubMed PMID: 30821019; PubMed Central PMCID: PMC6850587. 10: Watari R, Matsuda A, Ohnishi S, Hasegawa H. Minimal contribution of P-gp on the low brain distribution of naldemedine, a peripherally acting μ-opioid receptor antagonist. Drug Metab Pharmacokinet. 2019 Apr;34(2):126-133. doi: 10.1016/j.dmpk.2018.12.002. Epub 2018 Dec 23. PubMed PMID: 30770183. 11: Song X, Wang D, Qu X, Dong N, Teng S. A meta-analysis of naldemedine for the treatment of opioid-induced constipation. Expert Rev Clin Pharmacol. 2019 Feb;12(2):121-128. doi: 10.1080/17512433.2019.1570845. Epub 2019 Jan 24. Review. PubMed PMID: 30652502. 12: Saito Y, Yokota T, Arai M, Tada Y, Sumitani M. Naldemedine in Japanese patients with opioid-induced constipation and chronic noncancer pain: open-label Phase III studies. J Pain Res. 2018 Dec 24;12:127-138. doi: 10.2147/JPR.S175900. eCollection 2019. PubMed PMID: 30613161; PubMed Central PMCID: PMC6307491. 13: Inagaki M, Kume M, Tamura Y, Hara S, Goto Y, Haga N, Hasegawa T, Nakamura T, Koike K, Oonishi S, Kanemasa T, Kai H. Discovery of naldemedine: A potent and orally available opioid receptor antagonist for treatment of opioid-induced adverse effects. Bioorg Med Chem Lett. 2019 Jan 1;29(1):73-77. doi: 10.1016/j.bmcl.2018.11.007. Epub 2018 Nov 7. PubMed PMID: 30446313. 14: Ohnishi S, Fukumura K, Kubota R, Wajima T. Absorption, distribution, metabolism, and excretion of radiolabeled naldemedine in healthy subjects. Xenobiotica. 2019 Sep;49(9):1044-1053. doi: 10.1080/00498254.2018.1536815. Epub 2019 Jan 4. PubMed PMID: 30351180. 15: Kubota R, Fukumura K, Wajima T. Population Pharmacokinetics and Exposure-Response Relationships of Naldemedine. Pharm Res. 2018 Oct 2;35(11):225. doi: 10.1007/s11095-018-2501-7. PubMed PMID: 30280262; PubMed Central PMCID: PMC6182381. 16: Hu K, Bridgeman MB. Naldemedine (Symproic) for the Treatment Of Opioid-Induced Constipation. P T. 2018 Oct;43(10):601-627. PubMed PMID: 30271103; PubMed Central PMCID: PMC6152697. 17: Shikada Y, Emi Y, Kometani T, Ochiai T, Fujii M, Noda Y, Kajiwara M, Ikeda M, Asonuma S, Mori M. [A New Twist on the Administration of Naldemedine for Opioid-Induced Constipation in an Outpatient]. Gan To Kagaku Ryoho. 2018 Jul;45(7):1075-1079. Japanese. PubMed PMID: 30042276. 18: Katakami N, Harada T, Murata T, Shinozaki K, Tsutsumi M, Yokota T, Arai M, Tada Y, Narabayashi M, Boku N. Randomized phase 3 and extension studies: Efficacy and impacts on quality of life of naldemedine in subjects with opioid-induced constipation and cancer. Ann Oncol. 2018 Apr 18. doi: 10.1093/annonc/mdy118. [Epub ahead of print] PubMed PMID: 29912271; PubMed Central PMCID: PMC6005145. 19: Webster LR, Nalamachu S, Morlion B, Reddy J, Baba Y, Yamada T, Arjona Ferreira JC. Long-term use of naldemedine in the treatment of opioid-induced constipation in patients with chronic noncancer pain: a randomized, double-blind, placebo-controlled phase 3 study. Pain. 2018 May;159(5):987-994. doi: 10.1097/j.pain.0000000000001174. PubMed PMID: 29419653; PubMed Central PMCID: PMC5916485. 20: Yagi Y, Kosugi K, Tanimoto T. Randomized Phase III and Extension Studies of Naldemedine in Patients With Opioid-Induced Constipation and Cancer. J Clin Oncol. 2018 Apr 1;36(10):1049-1050. doi: 10.1200/JCO.2017.76.9349. Epub 2018 Feb 6. PubMed PMID: 29406801.