Mirodenafil

• CAT Number: I005168
• CAS Number: 862189-95-5
• Molecular Formula: C26H37N5O5S
• Molecular Weight: 531.67
• Purity: ≥95%
• Target: PDE
• Solubility: 10 mM in DMSO
• Storage: Store at -20C
• IUPAC Name: 5-ethyl-2-[5-[4-(2-hydroxyethyl)piperazin-1-yl]sulfonyl-2-propoxyphenyl]-7-propyl-3H-pyrrolo[3,2-d]pyrimidin-4-one
• InChI: InChI=1S/C26H37N5O5S/c1-4-7-19-18-30(6-3)24-23(19)27-25(28-26(24)33)21-17-20(8-9-22(21)36-16-5-2)37(34,35)31-12-10-29(11-13-31)14-15-32/h8-9,17-18,32H,4-7,10-16H2,1-3H3,(H,27,28,33)
• InChIKey: MIJFNYMSCFYZNY-UHFFFAOYSA-N
• SMILES: CCCC(C1=C2C(O)=NC(C3=C(OCCC)C=CC(S(N4CCN(CCO)CC4)(=O)=O)=C3)=N1)=CN2CC

Mirodenafil(CAS: 862189-95-5) is a phosphodiesterase type 5 (PDE-5) inhibitor developed for the treatment of erectile dysfunction.

Mirodenafil is a newly developed oral phosphodiesterase type 5 inhibitor. Mirodenafil, in doses of 50 or 100 mg, significantly improved erectile function and were well tolerated in a representative population of Korean men with broad-spectrum ED of various etiologies and severities. The concurrent administration of mirodenafil with alcohol was not associated with clinically significant hemodynamic changes in these healthy male volunteers in Korea. The pharmacoki-netics of mirodenafil were not significantly altered by this concurrent administration. Mirodenafil administered with alcohol had a tolerability profile comparable to that of mirodenafil alone. In these healthy Korean male volunteers, the coadministration of ketoconazole and rifampicin resulted in significant changes in systemic exposure to mirodenafil.

Overview of Clinical Research

Originator: SK Chemicals
Developer: In2Gen; SK Chemicals
Class: Erectile dysfunction therapies; Piperazines; Pyrimidinones; Small molecules; Sulfones
Mechanism of Action: Type 5 cyclic nucleotide phosphodiesterase inhibitors
Orphan Drug Status: No
New Molecular Entity: Yes

Reference

[1]. World J Mens Health. 2014 Apr;32(1):18-27. doi: 10.5534/wjmh.2014.32.1.18. Epub 2014 Apr 25.
Mirodenafil for the treatment of erectile dysfunction: a systematic review of the literature.
Park HJ(1), Moon KH(2), Lee SW(3), Lee WK(4), Kam SC(5), Lee JH(6), Park NC(1).
Author information: (1)Department of Urology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea. (2)Department of Urology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea. (3)Department of Urology, Hanyang University Guri Hospital, Guri, Korea. (4)Department of Urology, Chuncheon Sacred Heart Hospital, Hallym Unversity College of Medicine, Chuncheon, Korea. (5)Department of Urology, Gyeongsang National University School of Medicine, Jinju, Korea. (6)Department of Urology, National Police Hospital, Seoul, Korea.
Phosphodiesterase type 5 (PDE5) inhibitors are the most commonly used treatment for erectile dysfunction (ED). Since the launch of sildenafil, several drugs-including mirodenafil, sildenafil citrate (sildenafil), tadalafil, vardenafil HCL (vardenafil), udenafil, and avanafil-have become available. Mirodenafil is a newly developed pyrrolopyrimidinone compound, which is a potent, reversible, and selective oral PDE5 inhibitor. Mirodenafil was launched in Korea in 2007, and an orally disintegrating film of mirodenafil was developed in 2011 for benefitting patients having difficulty in swallowing tablets. This study aimed to review the pharmacokinetic characteristic profile of mirodenafil and report evidence on its efficacy in the case of ED. In addition, we reviewed randomized controlled studies of mirodenafil's daily administration and efficacy for lower urinary tract symptoms.
DOI: 10.5534/wjmh.2014.32.1.18 PMCID: PMC4026230 PMID: 24872948

[2]. Ther Adv Urol. 2016 Apr;8(2):100-17. doi: 10.1177/1756287215625408. Epub 2016 Jan 19.
A review of the efficacy and safety of mirodenafil in the management of erectile dysfunction.
Cho MC(1), Paick JS(2).
Author information: (1)Department of Urology, Seoul National University Boramae Medical Center, Seoul, Korea. (2)Department of Urology, Seoul National University College of Medicine, 28, Yongon-Dong, Chongno-Ku, Seoul 110-744, Korea.
Erectile dysfunction (ED) is a common disorder that can jeopardize quality of life and the partnership of patients and their sexual partners. The advent of oral phosphodiesterase type 5 inhibitors (PDE5Is) has revolutionized a treatment for ED, and they are recognized as the first-line therapy for ED, regardless of its etiology. Mirodenafil, a second-generation PDE5I, has biochemical profiles such as high affinity for PDE5 and high selectivity for PDE5 over other PDE isoforms, compared to other existing PDE5Is such as sildenafil, vardenafil and tadalafil. Available evidence has suggested that doses of 50 and 100 mg mirodenafil effectively improve ED [with improvements in the erectile function domain of the International Index of Erectile Function (IIEF-EF) scores, positive responses to questions 2 of the Sexual Encounter Profiles (SEP2) and questions 3 of the Sexual Encounter Profiles (SEP3): 7.6-11.6 points, 27.72-38.98% and 44.20-67.33%, respectively] in a broad range of patient populations with ED of a variety of underlying etiologies, severities and ages, without any serious treatment-related adverse effects. In the treatment of diabetic ED, a traditionally difficult-to-treat population, 100 mg mirodenafil has been reported to offer favorable efficacy (with improvements in the IIEF-EF scores, and positive responses to the SEP2 and the SEP3: 9.3 points, 36.1% and 61.8%, respectively) and tolerability (mild adverse effects of less than 19.6%), which are comparable with results from clinical studies on other PDE5Is. Mirodenafil appears to be effective, safe and well tolerated in men with both ED and hypertension or lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) who are taking concomitant antihypertensive medications or α1-blockers. Furthermore, recent evidence has indicated that mirodenafil may be a potential option for chronic dosing in the treatment of ED despite its short half-life (T 1/2). Most of the available clinical studies have reported that adverse effects (up to 53.7%) caused by 50 and 100 mg mirodenafil are mild or moderate in severity, with headache (1.8-14.8%) and flushing (6.7-24.1%) being the most common. Due to the pharmacodynamic profiles of mirodenafil, its tolerability is expected to be somewhat better than those of the other PDE5Is. However, further well designed studies with larger cohorts of different ethnicities, flexible dosing schedules and long-term follow up are necessary to confirm the favorable efficacy and tolerability profiles of mirodenafil for the treatment of ED.
DOI: 10.1177/1756287215625408 PMCID: PMC4772359 PMID: 27034723

[3]. Int Neurourol J. 2015 Mar;19(1):19-26. doi: 10.5213/inj.2015.19.1.19. Epub 2015 Mar 26.
Mirodenafil prevents bladder dysfunction induced by chronic bladder ischemia in rats.
Choi H(1), Bae JH(1), Shim JS(1), Park JY(1), Moon du G(2), Lee JG(3).
Author information: (1)Department of Urology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea. (2)Department of Urology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea. (3)Department of Urology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea.
PURPOSE: To investigate the protective effect of mirodenafil on bladder function in a rat model of chronic bladder ischemia (CBI). METHODS: Twenty-four Sprague-Dawley rats were randomized to three groups: untreated, sham-operated rats (control group); untreated, CBI model rats (CBI group); and CBI rats treated daily with 4 mg/kg mirodenafil (CBI+mirodenafil group). The CBI and CBI+mirodenafil groups underwent endothelial injury to the iliac arteries and were fed a 2% cholesterol diet after injury. Four weeks after surgery, the CBI+mirodenafil group started daily treatment with mirodenafil for four weeks. Eight weeks after surgery, continuous in vivo cystometry and in vivo organ bath studies of detrusor muscle strips were performed. RESULTS: in vivo cystometry revealed that the rats in the CBI group had a significantly higher micturition frequency, lower bladder capacity, and lower compliance than the rats in the control and CBI+mirodenafil groups. The detrusor muscle strip study showed that the magnitude of the carbachol-induced contractile response was significantly lower in the CBI group compared to either the control or CBI+mirodenafil group. Addition of daily mirodenafil after induction of CBI decreased the contractile response, compared to untreated CBI rats. CBI induced submucosal fibrosis and degenerative changes in bladder walls, which was reversed by the addition of mirodenafil. CONCLUSIONS: Daily treatment with mirodenafil showed protective effects against bladder dysfunction resulting from CBI in rats.
DOI: 10.5213/inj.2015.19.1.19 PMCID: PMC4386487 PMID: 25833477

[4]. J Pharm Biomed Anal. 2009 Feb 20;49(2):513-8. doi: 10.1016/j.jpba.2008.11.004. Epub 2008 Nov 13.
Determination of mirodenafil and sildenafil in the plasma and corpus cavernous of SD male rats.
Lee SK(1), Kim Y, Kim TK, Im GJ, Lee BY, Kim DH, Jin C, Yoo HH.
Author information: (1)Doping Control Center, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea.
The purpose of the present study was to determine sildenafil and a novel PDE-5 inhibitor, mirodenafil in the plasma and corpus cavernosum tissue of rats to compare their pharmacokinetic properties. The concentrations of mirodenafil and sildenafil in the rat plasma and corpus cavernosum tissue samples were analyzed using LC-MS/MS after a single oral administration at a dose of 40mg/kg to rats. Although the T(max), Tlambda(1/2) and MRT were not different between mirodenafil and sildenafil, the C(max) and AUC of mirodenafil were significantly higher than those of sildenafil in the plasma and corpus cavernosum tissue. Consequently mirodenafil remained longer than sildenafil in the plasma and tissue. This may provide pharmacokinetic evidence for assessment of the in vivo efficacy of mirodenafil and sildenafil.
DOI: 10.1016/j.jpba.2008.11.004 PMID: 19095395 [Indexed for MEDLINE]

[5]. Biopharm Drug Dispos. 2011 Jan;32(1):38-49. doi: 10.1002/bdd.737. Epub 2010 Nov 29.
Pharmacokinetics of mirodenafil and its two metabolites, SK3541 and SK3544, in spontaneously or DOCA-salt-induced hypertensive rats.
Lee YS(1), Choi YH, Yoon IS, Kim TK, Ryu KH, Lee BY, Lee MG.
Author information: (1)College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
Hypertension is the most common comorbidity and major risk factor in patients with erectile dysfunction. The pharmacokinetics of mirodenafil, used for the treatment of erectile dysfunction, after the intravenous and oral administration (20 mg/kg) to 6-week-old rats (with blood pressure within the normotensive range) and 16-week-old spontaneously hypertensive rats (SHRs) and their age-matched control normotensive Kyoto-Wistar (KW) rats, and 16-week-old deoxycorticosterone acetate-salt-induced hypertensive rats (DOCA-salt rats) and their age-matched control Sprague-Dawley (SD) rats were compared. It was found that time-averaged renal clearance (Cl(r)) was of minor importance and that time-averaged non-renal clearance (Cl(nr)) was dominant. In both 6- and 16-week-old SHRs, the Cl(nr)s and areas under the curve (AUCs) of intravenous mirodenafil were significantly smaller and greater than those of the controls, but in 16-week-old DOCA-salt rats, they were comparable to the controls. Although the AUC of oral mirodenafil in 16-week-old SHRs was comparable to the controls, the Cl(nr)s (or total body clearances, Cls) of intravenous mirodenafil and intestinal intrinsic clearances were significantly smaller than the controls and comparable to the controls for both 6- and 16-week-old SHRs, unlike in the 16-week-old DOCA-salt rats. The above data suggest that the significantly smaller Cl(nr) and greater AUC of intravenous mirodenafil and comparable AUC of oral mirodenafil in 16-week-old SHR could be due to the hereditary characteristics of SHRs, and not due to the hypertensive state itself.
DOI: 10.1002/bdd.737 PMID: 21162118 [Indexed for MEDLINE]