DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Mazisotine
CAS 1638588-92-7
MF C16H23N3O2 MW 289.37 g/mol
(1S,5R)-N-[2-methyl-1-[(3-methyl-2-pyridinyl)oxy]propan-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxamide
rac-(1R,5S,6R)-N-{2-methyl-1-[(3-methylpyridin-2-yl)oxy]propan-2-yl}-3-azabicyclo[3.1.0]hexane-6-carboxamide
(1R,5S,6r)-N-{2-methyl-1-[(3-methylpyridin-2-yl)oxy]propan-2-yl}-3-azabicyclo[3.1.0]hexane-6-carboxamide
somatostatin receptor receptor agonist, LY3556050, CNTX-0290, LY 3556050, CNTX 0290, D3M32WP3MH
Mazisotine (also known as LY3556050 or CNTX-0290) is an experimental, non-opioid chemical compound designed to treat chronic and neuropathic pain. It functions as a selective somatostatin receptor 4 (SSTR4) agonist, meaning it activates specific peripheral nerve pathways to block pain signals without activating the central nervous system’s opioid receptors.
While it showed early promise in animal models, Eli Lilly and Company removed mazisotine from its clinical development pipeline after disappointing results in Phase II clinical trials. It currently remains in use strictly as a chemical tool for laboratory pain research.
Key Facts and Clinical History
- Mechanism of Action: It binds to and activates SSTR4. This triggers a cellular response that suppresses pain and inflammation in peripheral sensory neurons.
- Intended Indications: It was being evaluated to treat diabetic peripheral neuropathic pain, osteoarthritis pain, and chronic low back pain.
- Development Partners: The compound was originally licensed by Eli Lilly from Centrexion Therapeutics in 2019 for an upfront fee of $47.5 million.
- Discontinuation: In mid-2025, Eli Lilly officially dropped the drug. Phase II clinical trials revealed that its efficacy did not meet the high success thresholds required to continue human testing.
- Side Effects: In clinical studies, reported treatment-emergent adverse effects were generally mild to moderate. They included constipation, nausea, dizziness, fatigue, and headaches.
Mazisotine (LY3556050, CNTX-0290) is a chemical compound which acts as an agonist at somatostatin receptor 4. It has analgesic effects and has been researched for the treatment of pain associated with arthritis and neuropathic pain. It was not pursued for human medical use following disappointing results in Phase II clinical trials, but continues to be used in research into the role of SST4 receptors in pain perception.[1][2]
- A Study of LY3556050 in Adult Participants With Diabetic Peripheral Neuropathic PainCTID: NCT06074562Phase: Phase 2Status: CompletedDate: 2025-07-03
- Chronic Pain Master Protocol (CPMP): A Study of LY3556050 in Participants With OsteoarthritisCTID: NCT04627038Phase: Phase 2Status: CompletedDate: 2023-11-02
- Chronic Pain Master Protocol (CPMP): A Study of LY3556050 in Participants With Diabetic Peripheral Neuropathic PainCTID: NCT04707157Phase: Phase 2Status: TerminatedDate: 2023-11-02
- Chronic Pain Master Protocol (CPMP): A Study of LY3556050 in Participants With Chronic Low Back PainCTID: NCT04874636Phase: Phase 2Status: CompletedDate: 2023-11-02
- A Study of Effect of LY3556050 on Metformin in Healthy ParticipantsCTID: NCT05615467Phase: Phase 1Status: CompletedDate: 2023-01-18
- A Study of Single and Repeated Doses of LY3556050 in Healthy ParticipantsCTID: NCT05341102Phase: Phase 1Status: CompletedDate: 2022-04-22
- A Study of LY3556050 in Healthy ParticipantsCTID: NCT04156750Phase: Phase 1Status: CompletedDate: 2020-08-19
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2025096300&_cid=P12-MQYLW5-94119-1
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=US214328185&_cid=P12-MQYLW3-94084-1
PAT
reparation 1
[0081] Methyl (E)-4-((4-methylphenyl)sulfonamido)but-2-enoate
[0082] Methyl 4-bromobut-2-enoate (36.29g, 202.7mmol) was dissolved in MeCN (500 mL) at 15-25 ºC. tert-Butyl tosylcarbamate (50.00 g, 184.3 mmol) was added at 15-25 ºC. K2CO3 (30.57 g, 221.2mmol) and KI (3.06 g, 202.7 mmol) were added to the solution at 15-25 ºC, and warmed under nitrogen at 30 ºC for 20 hrs. The solution was cooled to 20 ºC and the mixture filtered. The filtered residue was washed with MeCN (100 mL) to give methyl (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoate. TFA (101.03 g, 886.06 mmol) was added to the methyl (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoate in MeCN solution (483.72 g, 143 mmol) and heated to 55-60 ºC for 16 hrs. The reaction solution was concentrated in vacuo to ~50 mL and solvent exchanged with toluene (2 x 250 mL). Toluene (500 mL) was added followed by EtOAc (50 mL) at 15-25 °C, and heated to 60 ºC for 1 hr., then cooled to 0 ºC for 12 hrs. The solution was filtered, and the wet cake was rinsed with n-heptane (50 mL). The cake was dried in vacuum at 50 ºC to give the title compound (37.85 g, 74.4%) as a white solid.1H NMR (CDCl3) δ 7.68 (d, J = 8.0Hz, 2H) 7.25 (d, J = 8.0Hz, 2H) 6.71 (dt, J = 15.6, 5.2Hz, 1H) 5.88 (dt, J = 15.6, 1.6Hz, 1H) 4.55 (t, J = 6.4Hz, 1H) 3.71 – 3.67 (m, 2H) 3.65 (s, 3H) 2.37 (s, 3H); HRMS (ESI+) Calculated for [C12H15NO4S+H] +: 270.0795, Found: 270.0788 (M+H).
Preparation 2
[0083] (1R,5S,6r)-3-Tosyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid
0084] Methyl (E)-4-((4- 2-enoate (51.90 g) was dissolved in 2-MeTHF (600mL) at 0 ºC . Added (2-bromoethyl)diphenylsulfonium triflate (36.50 g), KF (6.47 g), KOH (18.75 g) to the solution at 0 ºC. Warmed the solution to 15 ºC for 22 hrs. then 30 ºC for 3 hrs. Added water (100 mL) and MeOH (100 mL) into the solution. Added LiOH.H2O (4.77 g) and stirred at 30 ºC for 16 hrs. Cooled to 15-25oC and added n-heptane (100 mL). Stirred at 15-25oC for 10 min. Separated and collected the aqueous phase and washed the aqueous phase with n-heptane/2-MeTHF (50 mL/200 mL × 2). Concentrated the aqueous phase in vacuo to ~50 mL and added 3M aq. HCl
dropwise to adjust pH to 1~2. Stirred the mixture at 20-30 ºC for 2 hrs. Filtered the solution and rinsed through with EtOH/H2O (15 mL1:4). Dried the wet cake at 45 ºC for 8-10 hrs. to give the title compound as white solid (20.37 g, 65%) 1H NMR (CDCl3) δ 7.67 (d, J = 8.2 Hz, 2 H) 7.34 (d, J = 8.2 Hz, 2 H) 3.63 (d, J = 9.4 Hz, 2 H) 3.12 (d, J = 9.4 Hz, 2 H) 2.46 – 2.40 (m, 4 H) 2.07 – 2.01 (m, 2 H); HRMS (ESI+) Calcd. for [C13H15NO4S+H] +: 282.0795, Found: 282.0795 (M+H).
Preparation 3
[0085] 2-Methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine
0086] 2-Amino-2-methylpropan- mmol) was dissolved in toluene (250 mL) at 15-25 ºC. Added potassium tert-butoxide (60.59 g, 534.6 mmol) to the solution and warmed to 30-40 ºC. Added 2-fluoro-3-methylpyridine (50.00 g, 450.0 mmol) to the solution and warmed to 80 ºC. Stirred the mixture for 18 hrs. at 80 ºC. Cooled the mixture to 15-25 ºC, added water (100 mL) and stirred for 30 min. Separated the aqueous layer and washed the organics with 10% aq. NaCl (300 mL x 3). Added toluene (250 mL) to the organics and concentrated in vacuo to give the title compound as a liquid (107.50 g, 98%). 1H NMR (CDCl3) δ 7.92 – 7.82 (m, 1H) 7.32 – 7.22 (m, 1H) 6.74 – 6.66 (m, 1H) 3.97 (s, 3H) 2.14 (s, 3H) 1.15 (s, 6H).
Preparation 4
[0087] (1R,5S,6r)-N-(2-Methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-tosyl-3-azabicyclo[3.1.0]hexane-6-carboxamide
[0088] Dissolved
6-carboxylic acid (32.33 g, 88.2% purity) in toluene (320 mL) at 15~25 ºC. Added DMF (741.0 mg) and (COCl)2 (19.20 g) to the solution and heated to 45-55 ºC for 3~4 hrs. Concentrated the mixture in vacuo and exchanged with THF (100 mL × 2). Added THF (320 mL) and cooled to 0-10 ºC. Added 2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine (23.60 g), TEA (30.80 g), DMAP (620.0 mg) at 0-10 ºC then warmed to 15-25 ºC for 2~4 hrs.
Concentrated the mixture in vacuo and solvent exchanged with EtOH (140 mL × 2). Concentrated in vacuo to 140 mL and heated to 50 ºC until the solid was dissolved. Added water (210 mL) dropwise into the solution at 40 ºC. Cooled the solution to 10 ºC for 14 hrs. Filtered and rinsed with EtOH/H2O (75 mL, 1:1.5). Dried the wet cake at 45 ºC for 20 hrs. to give the title compound as a solid (41.87 g, 87.4%).1H NMR (CDCl3) δ 7.94 – 7.87 (m, 1 H) 7.60 (d, J=8.0 Hz, 2 H) 7.37 (d, J=6.6 Hz, 1 H) 7.26 (d, J=8.0 Hz, 2 H) 6.78 (dd, J=6.6, 5.0 Hz, 1 H) 6.48 (s, 1 H) 4.25 (s, 2 H) 3.52 (d, J=9.4 Hz, 2 H) 2.95 (d, J=9.4 Hz, 2 H) 2.39 – 2.33 (m, 3 H) 2.17 (s, 3 H) 1.84 (s, 2 H) 1.39 (s, 6 H); HRMS (ESI+) Calcd. for [C23H29N3O4S+H] +: 444.1952, Found: 444.2089 (M+H).
Preparation 5
[0089] (1R,5S,6r)-N-(2-Methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide
[0090] Dissolved 2-yl)oxy)propan-2-yl)-3-tosyl-3-azabicyclo[3.1.0]hexane-6-carboxamide (5.00 g) in MTBE (50 mL) under nitrogen. Cooled to -70-60 ºC and added dropwise 1M Ph2PK in THF (56 mL, 56 mmol) into the solution. Stirred the mixture for 6-8 hrs. at -70-60 ºC. Added 2M aq. HCl (50 mL) to the solution allowing the temperature to rise to 15-25 ºC. Separated and collected the aqueous phase and washed with 2-MeTHF (50 mL × 3). Added 2-MeTHF (50 mL) and adjusted the pH to 8~9 with K2CO3 powder. Separated and extracted the aqueous phase with 2-MeTHF (50 mL). Combined the organics and concentrated in vacuo to give the title compound as a yellow-brown solid (3.05 g, 89.4%) 1H NMR (CDCl3) δ 8.01 – 7.92 (m, 1 H) 7.45 – 7.36 (m, 1 H) 6.81 (dd, J=7.0, 5.0 Hz, 1 H) 6.39 (s, 1 H) 4.31 (s, 2 H) 3.09 – 2.89 (m, 4 H) 2.21 (s, 3 H) 1.94 – 1.86 (m, 2 H) 1.69 (s, 1 H) 1.47 (s, 6 H) 1.12 (t, J=2.8 Hz, 1 H); HRMS (ESI+) Calcd. for [C16H23N3O2+H] +: 290.1863, Found:
290.1917 (M+H).
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References
References
- Stevens R, Corradini L, Doods H (April 2019). “Preclinical Evaluation of Human Somatostatin Receptor 4 (hSSTR4) Agonist CNTX-0290 for Mixed Pain Conditions”. The Journal of Pain. 20 (4): S73. doi:10.1016/j.jpain.2019.02.092.
- Nguyen TH, Saito T, Chang W, Navarro A, Davies HM (March 2026). “Diastereoselective Cyclopropanation with Secondary Diazoacetamides to Access endo-Azabicyclo[3.1.0]hexane-6-carboxamides”. Organic Letters. 28 (9): 3063–3067. doi:10.1021/acs.orglett.6c00392. PMC 12973298. PMID 41729728.
 | |
| Clinical data | |
|---|---|
| Other names | LY3556050, CNTX-0290 |
| Identifiers | |
| IUPAC name | |
| CAS Number | 1638588-92-7 |
| PubChem CID | 86294067 |
| ChemSpider | 77005706 |
| UNII | D3M32WP3MH |
| ChEMBL | ChEMBL5874446 |
| Chemical and physical data | |
| Formula | C16H23N3O2 |
| Molar mass | 289.379 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
PAT
- Novel methods for the preparation of 3-azabicylco[3.1,0]hexane-6-carboxamide derivativesPublication Number: WO-2025096300-A1Priority Date: 2023-10-30
- Methods for the preparation and dose regimens for use of sstr4 agonists and salts thereofPublication Number: WO-2024191686-A1Priority Date: 2023-03-10
- Methods for the preparation and dose regimens for use of sstr4 agonists and salts thereofPublication Number: US-2024307349-A1Priority Date: 2023-03-10
- Methods for preparation and dose regimens for use of sstr4 agonists and salts thereofPublication Number: JP-2024170613-APriority Date: 2023-03-10
- Methods for the preparation of SSTR4 agonists and their salts and dosage regimens for usePublication Number: JP-7569953-B2Priority Date: 2023-03-10Grant Date: 2024-10-18
- Sstr4 agonist saltsPublication Number: US-2024067628-A1Priority Date: 2021-09-14
- SSTR4 agonist saltsPublication Number: US-11834435-B2Priority Date: 2021-09-14Grant Date: 2023-12-05
- New somatostatin receptor subtype 4 (sstr4) agonistsPublication Number: EP-2997021-B1Priority Date: 2013-05-17Grant Date: 2017-12-20
- Somatostatin receptor subtype 4 (SSTR4) agonistsPublication Number: US-9371282-B2Priority Date: 2013-05-17Grant Date: 2016-06-21
- Somatostatin receptor subtype 4 (SSTR4) agonistsPublication Number: US-10166214-B2Priority Date: 2013-05-17Grant Date: 2019-01-01
- New somatostatin receptor subtype 4 (sstr4) agonistsPublication Number: US-2019269650-A1Priority Date: 2013-05-17
- New somatostatin receptor subtype 4 (sstr4) agonistsPublication Number: WO-2014184275-A1Priority Date: 2013-05-17
- Somatostatin receptor subtype 4 (SSTR4) agonistsPublication Number: US-10675268-B2Priority Date: 2013-05-17Grant Date: 2020-06-09
- New Somatostatin receptor subtype 4 (SSTR4) agonistsPublication Number: US-2014343065-A1Priority Date: 2013-05-17
- Somatostatin receptor subtype 4 (SSTR4) agonistsPublication Number: US-9789082-B2Priority Date: 2013-05-17Grant Date: 2017-10-17
- New somatostatin receptor subtype 4 (sstr4) agonistsPublication Number: US-2017014381-A1Priority Date: 2013-05-17
- Somatostatin receptor subtype 4 (sstr4) agonistsPublication Number: US-2018092880-A1Priority Date: 2013-05-17
////////mazisotine, ANAX LABS, somatostatin receptor receptor agonist, LY3556050, CNTX-0290, LY 3556050, CNTX 0290, D3M32WP3MH, PAIN, NEUROPATHIC PAIN
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