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Sulfoaildenafil …. An analog of Sildenafil which has been used as an illegal adulterant in some dietary supplements

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Sulfoaildenafil

An analog of Sildenafil which has been used as an illegal adulterant in some dietary supplements.

856190-47-1  cas no

5-(5-(((3R,5S)-3,5-Dimethylpiperazin-1-yl)sulfonyl)-2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-7(4H)-thione

  • 7H-Pyrazolo(4,3-d)pyrimidine-7-thione, 5-(5-(((3R,5S)-3,5-dimethyl-1-piperazinyl)sulfonyl)-2-ethoxyphenyl)-1,6-dihydro-1-methyl-3-propyl-, rel-
  • Sildenafil thione
  • Thioaildenafil
  • UNII-33DX49E09G
    • C23-H32-N6-O3-S2
    • 504.6768

Sulfoaildenafil (thioaildenafil) is a synthetic chemical compound that is a structural analog of sildenafil (Viagra).[1] It was first reported in 2005,[2] and it is not approved by any health regulation agency. Like sildenafil, sulfoaildenafil is a phosphodiesterase type 5 inhibitor.

Sulfoaildenafil has been found as an adulterant in a variety of supplements which are sold as “natural” or “herbal” sexual enhancement products.[3][4][5][6] A range of designer analogues of USA FDA-approved inhibitors of type-5 cGMP-specific phosphodiesterase (PDE5), such as sildenafil and vardenafil, have been detected in recent years as adulturants in over-the-counter herbal aphrodisiac products and dietary supplements,[7][8][9] in an apparent attempt to circumvent both the legal restrictions on sale of erectile dysfunction drugs, which are prescription-onlymedicines in most Western countries, and the patent protection which prevents sale of these drugs by competitors except under license to their inventors.

Figure 1. Biological pathway of penile erection

These compounds have been demonstrated to display PDE5 inhibitory activity in vitro and presumably have similar effects when consumed, but have undergone no formal testing in either humans or animals, and as such represent a significant health risk to consumers of these products due to their unknown safety profile.[10] Some attempts have been made to ban these drugs as unlicensed medicines, but progress has been slow so far, as even in those jurisdictions which have laws targeting designer drugs, the laws are drafted to ban analogues of illegal drugs of abuse, rather than analogues of prescription medicines. However at least one court case has resulted in a product being taken off the market.[11]

Figure 2. PDE5 domains

In December 2010, the United States Food and Drug Administration (FDA) issued a warning to consumers about such products stating, “The FDA has found many products marketed as dietary supplements for sexual enhancement during the past several years that can be harmful because they contain active ingredients in FDA-approved drugs or variations of these ingredients.”[12]

Figure 3. PDE5 Domains

An analog of aildenafil, which is a potent and highly selective inhibitor of phosphodiesterase 5, was found in a dietary supplement marketed for enhancement of sexual function. The compound was isolated by silica gel column chromatography, and its structure was identified by means of 13C-NMR spectrometry, 1H-NMR spectrometry, high-resolution MS, and X-ray structure determination. The compound was identified to be sulfoaildenafil(other names: thioaildenafil, dimethyl sildenafil thione, and thiomethisosildenafil). Sulfoaildenafil is very similar to the compound thiohomosildenafil. As it is difficult to distinguish between them by LC-photodiode array detector analysis, ultra-performance LC (UPLC)/MS, ion trap LC/MS/MS (LC/IT-MS/MS), and GC/MS were performed. The mass spectra of thiohomosildenafil by UPLC/MS and LC/IT-MS/MS showed mass fragments of m/z 58, 72, and 355, and the mass spectrum by GC/MS showed mass fragments of m/z 56, 72, and 420. Some of these fragments had low intensities, but they were useful for distinguishing between the two compounds. The relationship between aildenafil (other names: dimethylsildenafil and methisosildenafil) and homosildenafil is similar to that between sulfoaildenafil and thiohomosildenafil. Therefore, these compounds were also examined.http://www.ncbi.nlm.nih.gov/pubmed/22320083
……………………………………………………….

Volume 50, Issue 2, 8 September 2009, Pages 228–231

Phosphodiesterase type 5 (PDE-5) inhibitors represent a class of drugs used primarily in the treatment of erectile dysfunction. Currently, three PDE-5 inhibitors have been approved by the U.S. Food and Drug Administration (FDA) for use in the United States: sildenafil citrate, tadalafil, and vardenafil hydrochloride trihydrate. A bulk material, labeled as an ingredient for a dietary supplement, was analyzed for the presence of PDE-5 inhibitors. The compound that was detected displayed structural similarities to sildenafil, and was characterized further using LC–MSn, FTICRMS, X-ray crystallography and NMR. The compound was given the name sulfoaildenafil. When compared to sildenafil, sulfoaildenafil contains a sulfur atom substitution for the oxygen atom in the pyrazolopyrimidine portion of the molecule, and a 3,5-dimethyl substitution on the piperazine ring, rather than the 4-methyl moiety. The X-ray crystallographic data indicate that the material in this sample is comprised of two polymorphs, which may affect the chemical and/or biological properties of any product formulated with this compound.

……………..

http://www.theresonance.com/2012/categories/pharmaceutical/adulterated-natural-products

……………….

Herbal Supplement for Erectile Dysfunction Found to Contain Thio Structural Analog of Sildenafil (Viagra)

A herbal supplement marketed to alleviate erectile dysfunction was recently submitted for testing in our laboratory because it was surprisingly effective considering it should only contain the traditional herbals utilized for this problem such as Oyster, 2-Deoxy-D Glucose, Barberry, Snow Lotus, Bombyx Mori L., Ginger Root, Salfron Crocus.

http://process-nmr.com/WordPress/?cat=5

References

  1.  Gratz, SR; Zeller, M; Mincey, DW; Flurer, CL (2009). “Structural characterization of sulfoaildenafil, an analog of sildenafil”. Journal of pharmaceutical and biomedical analysis 50 (2): 228–31. doi:10.1016/j.jpba.2009.04.003PMID 19427155.
  2. Li, Shuxin; Ren, Jianping; Zhao, Yanjin; Lv, Qiujun; Guo, Jinhua. Pyrazolopyrimidinethione Derivatives, Salts and Solvates thereof, Preparation Methods and Use thereof. WO 2005058899
  3.  Gryniewicz, CM; Reepmeyer, JC; Kauffman, JF; Buhse, LF (2009). “Detection of undeclared erectile dysfunction drugs and analogues in dietary supplements by ion mobility spectrometry”. Journal of pharmaceutical and biomedical analysis 49 (3): 601–6. doi:10.1016/j.jpba.2008.12.002PMID 19150190.
  4.  FDA warns consumers to avoid sexual enhancement pills, Sanjay Gupta, CNN, December 13th, 2010
  5.  Reepmeyer JC, d’Avignon DA (January 2009). “Structure elucidation of thioketone analogues of sildenafil detected as adulterants in herbal aphrodisiacs”. Journal of Pharmaceutical and Biomedical Analysis 49 (1): 145–50. doi:10.1016/j.jpba.2008.10.007PMID 19042103.
  6.  Balayssac S, Trefi S, Gilard V, Malet-Martino M, Martino R, Delsuc MA (November 2008). “2D and 3D DOSY (1)H NMR, a useful tool for analysis of complex mixtures: Application to herbal drugs or dietary supplements for erectile dysfunction”. Journal of Pharmaceutical and Biomedical Analysis 50 (4): 602–12. doi:10.1016/j.jpba.2008.10.034PMID 19108978.
  7.  Zou P, Oh SS, Hou P, Low MY, Koh HL (February 2006). “Simultaneous determination of synthetic phosphodiesterase-5 inhibitors found in a dietary supplement and pre-mixed bulk powders for dietary supplements using high-performance liquid chromatography with diode array detection and liquid chromatography-electrospray ionization tandem mass spectrometry”. J Chromatogr A 1104 (1-2): 113–22. doi:10.1016/j.chroma.2005.11.103PMID 16364350.
  8.  Gratz SR, Gamble BM, Flurer RA (2006). “Accurate mass measurement using Fourier transform ion cyclotron resonance mass spectrometry for structure elucidation of designer drug analogs of tadalafil, vardenafil and sildenafil in herbal and pharmaceutical matrices”. Rapid Commun. Mass Spectrom. 20 (15): 2317–27. doi:10.1002/rcm.2594PMID 16817245.
  9.  Hou P, Zou P, Low MY, Chan E, Koh HL (September 2006). “Structural identification of a new acetildenafil analogue from pre-mixed bulk powder intended as a dietary supplement”. Food Addit Contam 23 (9): 870–5. doi:10.1080/02652030600803856PMID 16901855.
  10.  Oh, SS; Zou, P; Low, MY; Koh, HL (2006). “Detection of sildenafil analogues in herbal products for erectile dysfunction.”. Journal of toxicology and environmental health. Part A 69 (21): 1951–8.doi:10.1080/15287390600751355PMID 16982533.
  11.  Venhuis, BJ; Blok-Tip, L; De Kaste, D (2008). “Designer drugs in herbal aphrodisiacs.”. Forensic Science International 177 (2–3): e25–7. doi:10.1016/j.forsciint.2007.11.007PMID 18178354.
  12.  FDA warns consumers to avoid Man Up Now capsulesUnited States Food and Drug Administration, Dec. 15, 2010

2D image of a chemical structure


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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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