171596-36-4

Basic information

• Product Name: Nortadalafil
• Synonyms: DeMethyltadalafil;N-DesMethyl Tadalafil;(6R,12aR)-6-(1,3-Benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione;(6R-trans)-6-(1,3-Benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione;Nortadalafil;Tadalafil IMpurity:IMpurity C;Pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-, (6R,12aR)-;(6R,12aR)-6-(1,3-Benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione, N-DesMethyl Tadalafil
• CAS NO: 171596-36-4
• Molecular Formula: C21H16N3O4
• Molecular Weight: 374.36944
• Product Categories: Aromatics;Drug Analogues;Heterocycles;Indole Derivatives;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 171596-36-4.mol
• Article Data: 6

Chemical Properties

• Melting Point: 285-290℃ (methanol )
• Boiling Point: 718.6±60.0 °C(Predicted)
• Appearance: yellow powder
• Density: 1.55±0.1 g/cm3 (20 oC 760 Torr)
• Storage Temp.: Inert atmosphere,Room Temperature
• Solubility: DMSO (Slightly), Methanol (Slightly, Sonicated)
• PKA: 13.53±0.40(Predicted)
• CAS DataBase Reference: Nortadalafil(CAS DataBase Reference)
• NIST Chemistry Reference: Nortadalafil(171596-36-4)
• EPA Substance Registry System: Nortadalafil(171596-36-4)

Safety Data

• Hazardous Substances Data: 171596-36-4(Hazardous Substances Data)

Usage

Uses

A N-desmethyl analogue of the human PDE5 inhibitor Tadalafil (T004500). A potential antiplasmodial drug.

Biological Activity

the cgmp-specific pde5 is the major pde isozyme in the corpus cavernosum, and controls penile erection. the pde5 inhibitors used in the clinic amplify the no-ccmp pathway and enhance the normal process leading to penile erection.nortadalafil is demethyl tadalafil, which is a pde5 inhibitor currently marketed in pill form for treating erectile dysfunction under the name cialis and for the treatment of pulmonary arterial hypertension under the name adcirca.

in vitro

tadalafil has been identified as a highly potent pde5 inhibitor (ic50 = 5 nm) with high selectivity for pde5 vs pde1-4 and pde6. it displays 85-fold greater selectivity vs pde6 than sildenafil [1].

in vivo

tadalafil showed profound and long-lasting blood pressure lowering activity (30 mmhg/>7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg) [1].

IC 50

n/a for nortadalafil; 5 nm for tadalafil

references

[1] daugan a, grondin p, ruault c, le monnier de gouville ac, coste h, linget jm, kirilovsky j, hyafil f, labaudinière r. the discovery of tadalafil: a novel and highly selective pde5 inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione analogues. j med chem. 2003;46(21):4533-42.[2] porst h, hell-momeni k, büttner h. chronic pde-5 inhibition in patients with erectile dysfunction - a treatment approach using tadalafil once-daily. expert opin pharmacother. 2012 jul;13(10):1481-94. doi: 10.1517/14656566.2012.693162.

Upstream product

• 120-57-0 piperonal 
• 495-76-1 piperonol 
• 4299-70-1 D-Tryptophan methyl ester 
• 171596-41-1 (1R,3R)-methyl 1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate 
• 14907-27-8 (R)-(+)-tryptophan methyl ester hydrochloride 
• 171489-59-1 methyl (1R,3R)-1-(3,4-methylenedioxyphenyl)-2-chloroacetyl-2,3,4,9-tetrahydro-9H-pyrido[3,4-b]indol-3-carboxylate 

Downstream Products

• 1295647-22-1 4-[3-[(6R,12aR)-6-benzo[1,3]dioxol-5-yl-1,4-dioxo-3,4,6,7,12,12a-hexahydro-1H-pyrazino[1',2':1,6]pyrido[3,4-b]indol-2-yl]benzyl]piperazine-1-carboxylic acid tert-butyl ester 
• 1295647-23-2 4-[4-[(6R,12aR)-6-benzo[1,3]dioxol-5-yl-1,4-dioxo-3,4,6,7,12,12a-hexahydro-1H-pyrazino[1',2':1,6]pyrido[3,4-b]indol-2-yl]phenyl]piperazine-1-carboxylic acid tert-butyl ester 
• 1295647-21-0 (6R,12aR)-6-benzo[1,3]dioxol-5-yl-2-(4-morpholin-4-ylmethylphenyl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione 
• 1295647-25-4 (6R,12aR)-6-benzo[1,3]dioxol-5-yl-2-(4-piperazin-1-ylphenyl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione hydrochloride 

Relevant articles and documents

Impact of Scaffold Exploration on Novel Dual-Acting Histone Deacetylases and Phosphodiesterase 5 Inhibitors for the Treatment of Alzheimer’s Disease

A novel systems therapeutics approach, involving simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylase (HDAC), has been validated as a potentially novel therapeutic strategy for the treatment of Alzheimer’s disease (AD). First-in-class dual inhibitors bearing a sildenafil core have been very recently reported, and the lead molecule 7 has proven this strategy in AD animal models. Because scaffolds may play a critical role in primary activities and ADME-Tox profiling as well as on intellectual property, we have explored alternative scaffolds (vardenafil- and tadalafil-based cores) and evaluated their impact on critical parameters such as primary activities, permeability, toxicity, and in vivo (pharmacokinetics and functional response in hippocampus) to identify a potential alternative lead molecule bearing a different chemotype for in vivo testing.

PDE5 inhibitors: An original access to novel potent arylated analogues of tadalafil

A method to access totally new analogues of tadalafil was explored. The Buchwald reaction was adapted and used to replace the methyl group of tadalafil by various aryl groups. Inhibition potencies on PDE5 of these analogues were determined and proved to be comparable to the one of tadalafil. Using the same route, compounds with the same level of activity but improved water solubility were produced by introducing a pyridine or a pyrimidine ring. This original route also opens access to new unpatented compounds.

Method of treating nitrate-induced tolerance

The present invention relates to methods for treating nitrate-induced tolerance in a mammal by administering a nitrate-induced tolerance treating amount of a compound of formulae (I), (II), (III) (IV), (V), (VI), (VII), (VIII), (IX), (XA) or (XB) as defined herein, or the pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates, solvates, active metabolites or stereoisomers thereof. The invention also relates to pharmaceutical compositions for the treatment of nitrate-induced tolerance in a mammal comprising a nitrate-induced tolerance treating amount of a compound of formulae (I), (II), (III) (IV), (V), (VI), (VII), (VIII), (IX), (XA) or (XB) as defined herein, or the pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates, solvates, active metabolites or stereoisomers thereof, and a pharmaceutically acceptable vehicle, diluent or carrier. The invention further relates to methods of preventing nitrate-induced tolerance in a mammal comprising administering a nitrate-induced tolerance preventing amount of a cGMP PDE inhibitor.