Mazindol

Clinical data
Trade names	Mazanor, Sanorex
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Routes of administration	By mouth
ATC code	A08AA05 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) BR: Class B2 (Anorectic drugs)[1] CA: Schedule IV DE: Anlage II (Authorized trade only, not prescriptible) US: Schedule IV
Pharmacokinetic data
Bioavailability	93%
Metabolism	Hepatic
Eliminationhalf-life	10–13 hours
Excretion	Renal
Identifiers
IUPAC name (±)-5-(4-chlorophenyl)-3,5-dihydro-2H-imidazo[2,1-a]isoindol-5-ol
CAS Number	22232-71-9 Y
PubChemCID	4020
IUPHAR/BPS	4797
DrugBank	DB00579 Y
ChemSpider	3880 Y
UNII	C56709M5NH
KEGG	D00367 Y
ChEMBL	ChEMBL781 Y
CompTox Dashboard(EPA)	DTXSID1023237
ECHA InfoCard	100.040.764
Chemical and physical data
Formula	C16H13ClN2O
Molar mass	284.74 g·mol−1
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
SMILES ClC1=CC=C(C2(C3=CC=CC=C3C4=NCCN42)O)C=C1
InChI InChI=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 Y Key:ZPXSCAKFGYXMGA-UHFFFAOYSA-N Y
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Mazindol, sold under the brand namesMazanor andSanorex, is anappetite suppressant.^[2] It was developed bySandoz-Wander in the 1960s.^[3] TheUS Food and Drug Administration approved mazindol in June 1973, butNovartis, the manufacturer, discontinued it in 1999 for reasons unrelated to its efficacy or safety.^[4]

Mazindol is used in short-term (i.e., a few weeks) treatment ofobesity, in combination with a regimen of weight reduction based oncaloric restriction,exercise, andbehavior modification in people with abody mass index greater than 30, or in those with a body mass index greater than 27 in the presence of risk factors such ashypertension,diabetes, orhyperlipidemia. 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 ofnarcolepsy andcataplexy.^[5] Studies beginning in the 1970s indicated that mazindol reduced sleep attacks and cataplexy with comparable efficacy toamphetamine, but with reduced cardiovascular side effects.^[5][6][7] In 2021, mazindol was identified as anorexin-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.^[5][8] Preclinical studies have also suggested potential neuroprotective effects in rat models of narcolepsy.^[5]

There is a Swiss study investigating its efficacy in treatingattention deficit hyperactivity disorder (ADHD).^[9]

Additional patented uses include for the treatment ofschizophrenia,^[10] reducing cravings forcocaine,^[11] and for the treatment of neurobehavioral disorders.^[12]

Mazindol is asympathomimetic amine, which is similar toamphetamine. It stimulates thecentral nervous system, which increasesheart rate andblood pressure, and decreasesappetite. 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 areuptake inhibitor ofnorepinephrine,dopamine, andserotonin. 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, andseizures.

An analogue of mazindol was reported that was stated to be less toxic than the parent drug from which it was derived.^[14] It is made from Chemrat (pindone).

From availableQSAR data, the following trends are apparent:^[16]

1. Removal of the tertiary alcohol improvesDAT andSERT binding without substantially reducingNET affinity. This compound has been called "mazindane".^[17]
2. Removal of thep-chlorine atom increases NET affinity and substantially reduces DAT and SERT affinity.
3. Expansion of theimidazoline ring to the corresponding six-membered homolog increases DAT affinity by ~10 fold.
4. Replacement of the phenyl moiety with a naphthyl ring system results in a ~50 fold increase in SERT affinity without significant decreases in NET or DAT affinities.
5. Halogenation of 3' and/or 4' position of the phenyl ring of mazindol results in increased potency at NET, DAT, and SERT.
6. Fluorination of the 7' position of the tricyclic phenyl ring results in a ~2 fold increase in binding affinity to DAT.

Mazindol analogs with phenyl ring substitutions^[b]

Compound	S. Singh's alphanumeric assignation (name)	R	R′	R′′	IC50 (nM) (Inhibition of [3H]WIN 35428 binding)	IC50 (nM) (Inhibition of [3H]DA uptake)	Selectivity uptake/binding
	(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

Mazindol Ring A homologues^[c]

Compound	S. Singh's alphanumeric assignation (name)	R	R′	IC50 (nM) (Inhibition of [3H]WIN 35428 binding)	IC50 (nM) (Inhibition of [3H]DA uptake)	Selectivity uptake/binding
	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

Miscellaneous mazindol analogues^[16]

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	-OCH2O-		OH	83 ± 29	0.62 ± 0.25	2.21 ± 0.3	37.7	0.3

Mazindol exhibits pH dependenttautomerization between the keto form and the cyclichemiaminal. 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.^[18]

The precursor for mazindol was described in the synthesis ofChlortalidone.

The synthesis of mazindol starts by reaction of a substituted benzoylbenzoic acid (1) withethylenediamine. The product3 can be rationalized as being anaminal from the initially formed monoamide2. This is then subjected to reduction withLiAlH₄ and-without isolation-air oxidation. Reduction probably proceeds to the mixed aminal/carbinolamine4; such a product would be expected to be in equilibrium with the alternate aminal5. 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 remove5 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 forattention-deficit hyperactivity disorder.^[23]

• Ciclazindol
• Setazindol
• Trazium
• Dazadrol
• AW-15'1129
• Serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI)

• 4-Chlorophenyl compounds
• Imidazolines
• Serotonin–norepinephrine–dopamine reuptake inhibitors
• Stimulants
• Sympathomimetic amines
• Tertiary alcohols
• Wakefulness-promoting agents

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