Synthesis and phosphodiesterase 5 inhibitory activity of novel phenyl ring modified sildenafil analogues

Kim, Dae Kee; Lee, Namkyu; Lee, Ju Young; Ryu, Do Hyun; Kim, Jae Sun; Lee, Suk Ho; Choi, Jin Young; Chang, Kieyoung; Kim, Young Woo; Im, Guang Jin; Choi, Won Son; Kim, Tae Kon; Ryu, Je Ho; Kim, Nam Ho; Lee, Kyoungrim

doi:10.1016/s0968-0896(01)00055-4

Cited by 25 publications

(11 citation statements)

References 18 publications

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“…These compounds exhibit minor structural alterations compared to their approved or commercial counterparts. Based on these structural similarities, it is reasonable to expect these analogs to exhibit similar biological activities [7][8][9]. The presence of analogs in herbal supplements or in unapproved drug products could pose a significant risk to public health, because these analogs are not declared on the labeling.…”

Section: Introductionmentioning

confidence: 99%

Structural characterization of sulfoaildenafil, an analog of sildenafil

Gratz

Zeller

Mincey

et al. 2009

Journal of Pharmaceutical and Biomedical Analysis

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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-MS(n), 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.

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Section: Introductionmentioning

confidence: 99%

Structural characterization of sulfoaildenafil, an analog of sildenafil

Gratz

Zeller

Mincey

et al. 2009

Journal of Pharmaceutical and Biomedical Analysis

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“…Several sildenafil analogues and related compounds were reported in the literature [5,6,7,8,9,10,11,12,13,14,15,16,17,18]. In the present work [19], we also report the synthesis of three novel analogues (Scheme 3) of sildenafil, namely (i) 5-[2-ethoxy-5-(4-methylpiperazinylsulfonyl)phenyl]-1-methyl-3-ethyl-1,6-dihydro-7 H -pyrazolo[4,3- d ]pyrimidin-7-one (sildenafil ethyl analogue, 4a ); (ii) 5-[2-ethoxy-5-(4-methylpiperazinylsulfonyl)phenyl]-1-methyl-3- n -butyl-1,6-dihydro-7 H -pyrazolo[4,3- d ]pyrimidin-7-one (sildenafil butyl analogue, 4b ); and (iii) 5-[2-ethoxy-5-(4-methylpiperazinylsulfonyl)phenyl]-1-methyl-3-isopropyl-1,6-dihydro-7 H -pyrazolo[4,3- d ]pyrimidin-7-one (sildenafil isopropyl analogue, 4c ) using the improved chlorosulfonation reaction.…”

Section: Resultsmentioning

confidence: 99%

A Facile, Improved Synthesis of Sildenafil and Its Analogues

et al. 2015

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This paper describes the facile synthesis of sildenafil citrate (1) and its related compounds through an improved chlorosulfonation reaction using chlorosulfonic acid and thionyl chloride. This synthesis results in pure sildenafil with high yield. The structures of the compounds were determined with infrared (IR), 1H-NMR and 13C-NMR spectroscopic methods, and high resolution mass spectroscopy (HRMS) analysis.

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“…It may also serve as a requirement for a small lipophilic substituent. A team from SK Chemicals 61 investigated if a fused-ring system such as in 1 could enhance the PDE5 inhibitory activity and selectivity compared with sildenafil (Fig. 3).…”

Section: E F F O R T S T O D I S C O V E R P D E 5 I N H I B I T O mentioning

confidence: 99%

Phosphodiesterase 5 (PDE 5) inhibitors for the treatment of male erectile disorder: Attaining selectivity versus PDE6

Pissarnitski¹

2005

Medicinal Research Reviews

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The role of phosphodiesterase type 5 (PDE5) in the mechanism of male erection has been well understood, and several drugs inhibiting this enzyme are being used for the treatment of erectile dysfunction (ED). Discovery of inhibitors with improved selectivity versus other PDE isozymes could lead to drugs with improved safety profile. Achievement of selectivity versus PDE6, co-inhibition of which results in disturbances of color perception, remains the most challenging aspect of current drug discovery programs. The present review describes several case studies, where significant (>100 fold) selectivity versus PDE6 has been attained via investigation of structure-activity relationships (SAR). Special attention is given to the chemical routes leading to novel chemotypes and allowing efficient exploration of their SAR's. Strategies for attaining inhibitor selectivity discussed below may be applicable for other drug discovery programs.

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Synthesis and phosphodiesterase 5 inhibitory activity of novel phenyl ring modified sildenafil analogues

Cited by 25 publications

References 18 publications

Structural characterization of sulfoaildenafil, an analog of sildenafil

Structural characterization of sulfoaildenafil, an analog of sildenafil

A Facile, Improved Synthesis of Sildenafil and Its Analogues

Phosphodiesterase 5 (PDE 5) inhibitors for the treatment of male erectile disorder: Attaining selectivity versus PDE6

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