| Watchedfields: | changed |
| Verifiedrevid: | 462100725 |
| Iupac Name: | (±)-5-(4-chlorophenyl)-3,5-dihydro-2H-imidazo[2,1-''a'']isoindol-5-ol |
| Image Class: | skin-invert-image |
| Width: | 200px |
| Width2: | 250px |
| Tradename: | Mazanor, Sanorex |
| Legal Au: | S4 |
| Legal Br: | B2 |
| Legal Br Comment: | [1] |
| Legal Ca: | Schedule IV |
| Legal Us: | Schedule IV |
| Legal De: | Anlage II |
| Legal Status: | Schedule IV (International) |
| Routes Of Administration: | By mouth |
| Bioavailability: | 93% |
| Metabolism: | Hepatic |
| Elimination Half-Life: | 10–13 hours |
| Excretion: | Renal |
| Iuphar Ligand: | 4797 |
| Cas Number: | 22232-71-9 |
| Atc Prefix: | A08 |
| Atc Suffix: | AA05 |
| Pubchem: | 4020 |
| Drugbank: | DB00579 |
| Chemspiderid: | 3880 |
| Unii: | C56709M5NH |
| Kegg: | D00367 |
| Chembl: | 781 |
| C: | 16 |
| H: | 13 |
| Cl: | 1 |
| N: | 2 |
| O: | 1 |
| Smiles: | ClC1=CC=C(C2(C3=CC=CC=C3C4=NCCN42)O)C=C1 |
| Stdinchi: | 1S/C16H13ClN2O/c17-12-7-5-11(6-8-12)16(20)14-4-2-1-3-13(14)15-18-9-10-19(15)16/h1-8,20H,9-10H2 |
| Stdinchikey: | ZPXSCAKFGYXMGA-UHFFFAOYSA-N |
| Chirality: | Racemic mixture |
Mazindol, sold under the brand names Mazanor and Sanorex, is a central nervous system (CNS) stimulant which is used as an appetite suppressant.[2] It was developed by Sandoz-Wander in the 1960s. The US Food and Drug Administration approved mazindol in June 1973, but Novartis, the manufacturer, discontinued it in 1999 for reasons unrelated to its efficacy or safety.[3]
Mazindol is used in short-term (i.e., a few weeks) treatment of obesity, in combination with a regimen of weight reduction based on caloric restriction, exercise, and behavior modification in people with a body mass index greater than 30, or in those with a body mass index greater than 27 in the presence of risk factors such as hypertension, diabetes, or hyperlipidemia. Mazindol is not currently available as a commercially marketed and FDA-regulated prescription agent for the treatment of obesity.
Off-label use of mazindol has demonstrated efficacy in treating symptoms of narcolepsy and cataplexy.[4] Studies beginning in the 1970s indicated that mazindol reduced sleep attacks and cataplexy with comparable efficacy to amphetamine, but with reduced cardiovascular side effects.[4] [5] [6] In 2021, mazindol was identified as an orexin-2 receptor (OX2R) agonist, providing a mechanistic explanation for its therapeutic action in narcolepsy, a condition often linked to orexin system dysfunction. This discovery has prompted further research interest, including the development of modified-release formulations and clinical trials such as the POLARIS program and phase 3 AMAZE trials.[4] [7] Preclinical studies have also suggested potential neuroprotective effects in rat models of narcolepsy.[4]
There is a Swiss study investigating its efficacy in treating attention deficit hyperactivity disorder (ADHD).[8]
Additional patented uses include for the treatment of schizophrenia,[9] reducing cravings for cocaine,[10] and for the treatment of neurobehavioral disorders.[11]
| Site | Ki (nM) | |
|---|---|---|
| 25.9 | ||
| 2.88 | ||
| SERT | 272 |
Mazindol is a sympathomimetic amine, which is similar to amphetamine. It stimulates the central nervous system, which increases heart rate and blood pressure, and decreases appetite. Sympathomimetic anoretics (appetite suppressants) are used in the short-term treatment of obesity. Their appetite-reducing effect tends to decrease after a few weeks of treatment. Because of this, these medicines are useful only during the first few weeks of a weight-loss program.
Although the mechanism of action of the sympathomimetics in the treatment of obesity is not fully known, these medications have pharmacological effects similar to those of amphetamines. Like other sympathomimetic appetite suppressants, mazindol is thought to act as a reuptake inhibitor of norepinephrine, dopamine, and serotonin. The recommended dosage is 2 mg per day for 90 days in patients 40 kg overweight and under; 4 mg a day in patients more than 50 kg overweight; divided into two doses separated by a 12-hour window between each dose.
Symptoms of a mazindol overdose include: restlessness, tremor, rapid breathing, confusion, hallucinations, panic, aggression, nausea, vomiting, diarrhea,irregular heartbeat, and seizures.
An analogue of mazindol was reported that was stated to be less toxic than the parent drug from which it was derived.[13] It is made from Chemrat (pindone).
From available QSAR data, the following trends are apparent:[14]
| (cocaine) | 89.1 ± 8 | 208 ± 12 | 2.3 | ||||
| (mazindol) | H | H | 4′-Cl | 8.1 ± 1.2 | 8.4 ± 1.3 | 1.0 | |
| 384a | H | H | H | 66.0 ± 8.9 | 124 ± 37 | 1.9 | |
| 384b | H | H | 4′-F | 13.3 ± 1.8 | 25.4 ± 2.7 | 1.9 | |
| 384c | H | 7-F | H | 29.7 ± 7.0 | 78 ± 46 | 2.6 | |
| 384d | H | H | 2′-Cl | 294 ± 6 | 770 ± 159 | 2.6 | |
| 384e | H | H | 3′-Cl | 4.3 ± 0.4 | 9.2 ± 5.3 | 2.1 | |
| 384f | CH3 | H | 4′-Cl | 50.4 ± 5.5 | 106 ± 5.6 | 2.1 | |
| 384g | H | 6-Cl | H | 57.2 ± 8.3 | 58 ± 6.4 | 1.0 | |
| 384h | H | 7-Cl | H | 85.4 ± 14 | 55.17 | 0.6 | |
| 384i | H | 7-F | 4′-Cl | 6.5 ± 1.2 | 15 ± 9 | 2.3 | |
| 384j | H | 7-Cl | 4′-F | 52.8 ± 8.7 | 53 ± 18 | 1.0 | |
| 384k | H | H | 2′,4′-Cl2 | 76.5 ± 1.11 | 92 ± 19 | 1.2 | |
| 384l | H | H | 3′,4′-Cl2 | 2.5 ± 0.5 | 1.4 ± 1.6 | 0.6 | |
| 384m | H | 7,8-Cl2 | 4′-Cl | 13.6 ± 1.5 | |||
| 384n | H | H | 2′-Br | 1340 ± 179 | |||
| 384o | H | H | 4′-Br | 2.6 ± 1.5 | 8.6 ± 3.5 | 3.3 | |
| 384p | H | H | 4′-I | 17.2 ± 0.9 | 14 ± 6.4 | 0.8 |
| 388a | H | H | 5.8 ± 1.6 | 18 ± 11 | 3.1 | |
| 388b | H | 2′-F | 23.2 ± 1.7 | 89 ± 2.8 | 3.8 | |
| 388c | H | 3′-F | 2.0 ± 0.02 | 3.1 ± 1.8 | 1.6 | |
| 388d | H | 4′-F | 3.2 ± 1.7 | 8.5 ± 4.9 | 0.4 | |
| 388e | H | 3′-Cl | 1.0 ± 0.2 | 1.3 ± 0.14 | 1.3 | |
| 388f | H | 4′-Cl | 1.7 ± 0.2 | 1.4 ± 0.35 | 0.8 | |
| 388g | CH3 | 4′-Cl | 6.3 ± 4.5 | 1.7 ± 1.6 | 0.3 | |
| 389a | H | 5.9 ± 0.1 | 11 ± 3.2 | 2.0 | ||
| 389b | 4′-Cl | 1.5 ± 0.1 | 3.4 ± 2.3 | 2.3 | ||
| 389c | 3′,4′-Cl2 | 1.7 ± 0.1 | 0.26 ± 0.16 | 0.2 |
| Structure | n | R | R' | R" | hSERT | hNET | hDAT | SERT/DAT Selectivity | NET/DAT Selectivity |
|---|---|---|---|---|---|---|---|---|---|
| 1 | Cl | H | OH | 94 ± 32 | 4.9 ± 0.5 | 43 ± 20 | 2.2 | 0.1 | |
| 1 | Cl | H | H | 15 ± 5 | 6.9 ± 1.5 | 6.0 ± 0.7 | 2.5 | 1.2 | |
| 1 | H | H | OH | 2140 ± 450 | 2.8 ± 0.92 | 730 ± 180 | 2.9 | 0.004 | |
| 1 | Naphthyl | OH | 1.8 ± 1.3 | 4.5 ± 1.5 | 66 ± 10 | 0.03 | 0.07 | ||
| 2 | Cl | H | OH | 53 ± 7 | 4.9 ± 0.5 | 3.7 ± 0.4 | 14.3 | 1.3 | |
| 2 | OH | H | OH | 60 ± 19 | 1.9 ± 0.15 | 59.0 ± 3.6 | 1 | 0.03 | |
| 2 | OMe | H | OH | 94 ± 34 | 4.1 ± 1.4 | 30.4 ± 2.4 | 3.1 | 0.1 | |
| 2 | colspan=2 | -OCH2O- | OH | 83 ± 29 | 0.62 ± 0.25 | 2.21 ± 0.3 | 37.7 | 0.3 | |
Mazindol exhibits pH dependent tautomerization between the keto form and the cyclic hemiaminal. Mazindol exists in the tricyclic (-ol) form in neutral media and undergoes protonation to the benzophenone tautomer in acidic media. QSAR studies have indicated that the ability of mazindol to inhibit NE and DA reuptake may be mediated by the protonated (benzophenone) tautomer.[16]
The precursor for mazindol was described in the synthesis of Chlortalidone.The synthesis of mazindol starts by reaction of a substituted benzoylbenzoic acid (1) with ethylenediamine. The product 3 can be rationalized as being an aminal from the initially formed monoamide 2. This is then subjected to reduction with LiAlH4 and-without isolation-air oxidation. Reduction probably proceeds to the mixed aminal/carbinolamine 4; such a product would be expected to be in equilibrium with the alternate aminal 5. The latter would be expected to predominate because of the greater stability of aldehyde aminals over the corresponding ketone derivatives. Air oxidation of the tetrahydroimidazole to the imidazoline will then remove 5 from the equilibrium. There is thus obtained the anorectic agent mazindol (6). The synthesis of homomazindol (the six-member ring A homologue) is accomplished by substitution of 1,2-diaminoethane with 1,3-diaminopropane.
An alternative synthesis was described:2-Phenyl-2-Imidazoline [936-49-2] (3)Methyl 4-Chlorobenzoate [1126-46-1] (4)
As of 2016 mazindol was being studied in clinical trials for attention-deficit hyperactivity disorder.[17]