Common name: Imidafenacin; Staybla; Uritos; ONO-8025; KRP-197; KRP 197; ONO 8025
Trademarks: Staybla; Uritos
Molecular Formula: C20H21N3O
CAS Registry Number: 170105-16-5
CAS Name: 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide
Molecular Weight: 319.40
SMILES: CC1=NC=CN1CCC(C2=CC=CC=C2)(C3=CC=CC=C3)C(=O)N
InChI Key: SQKXYSGRELMAAU-UHFFFAOYSA-N
InChI:InChI=1S/C20H21N3O/c1-16-22-13-15-23(16)14-12-20(19(21)24,17-8-4-2-5-9-17)18-10-6-3-7-11-18/h2-11,13,15H,12,14H2,1H3,(H2,21,24)
Activity: Muscarinic M1/M3 Antagonist; Muscarinic Antagonist; Treatment of Overactive Bladder; Treatment of OAB
Status: Launched 2007
Originator: Kyorin/Ono Pharmaceuticals
Imidafenacin synthesis: Bioorg Med Chem 1999, 7(6), 1151-1161 (also Ref. 4)
Procedure:
Alkylation of diphenylacetonitrile with dibromoethane provided bromide. This was condensed with 2-methylimidazole in the presence of TEA (triethylamine) in DMF to afford the substituted imidazole. Finally, hydrolysis of the cyano group of with 70% sulfuric acid produced the target amide.
Procedure from Ref. 4
Step a: 4-Bromo-2,2-diphenylbutyronitrile (3.00 g, 10.0 mmol), 2-methylimidazole (2.46 g, 30.0 mmol), triethylamine (1.40 ml, 10.0 mmol) and dimethylformamide (50 ml) were mixed and stirred under heat for 30 hours at 150 °C in a sealed tube. The solution was poured into water, and was extracted with benzene. The organic extract was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel chromatography (elution solvent; dichloromethane:ethanol = 10:1) and formed hydrochloric salt with hydrogen chloride-ether solution. Then, this was recrystallized from ethyl acetate to give 2.60 g of 4-(2-Methyl-1-imidazolyl)-2,2-diphenylbutyronitrile hydrochloride as a colorless powder. Yield: 77 %.
Step b: 4-(2-Methyl-1-imidazolyl)-2,2-diphenylbutyronitrile (7.83 g, 26.0 mmol) and 70 % sulfuric acid (50 ml) were mixed and stirred for 40 minutes at 140 to 150 °C. The solution was made alkaline and extracted with a mixed solvent (5:1) of chloroform with ethanol. The organic extract was dried over anhydrous sodium sulfate and then concentrated. The residue was recrystallized from ethyl acetate-ethanol to give 2.02 g of 4-(2-Methyl-1-imidazolyl)-2,2-diphenylbutylamide as colorless needle-like crystals. Yield: 32 %, Melting point: 189 - 190 °C
Imidafenacin synthesis: Bioorg Med Chem 1999, 7(6), 1151-1161 (also Ref. 4)
Procedure:
Alkylation of diphenylacetonitrile with dibromoethane provided bromide. This was condensed with 2-methylimidazole in the presence of TEA (triethylamine) in DMF to afford the substituted imidazole. Finally, hydrolysis of the cyano group of with 70% sulfuric acid produced the target amide.
Procedure from Ref. 4
Step a: 4-Bromo-2,2-diphenylbutyronitrile (3.00 g, 10.0 mmol), 2-methylimidazole (2.46 g, 30.0 mmol), triethylamine (1.40 ml, 10.0 mmol) and dimethylformamide (50 ml) were mixed and stirred under heat for 30 hours at 150 °C in a sealed tube. The solution was poured into water, and was extracted with benzene. The organic extract was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel chromatography (elution solvent; dichloromethane:ethanol = 10:1) and formed hydrochloric salt with hydrogen chloride-ether solution. Then, this was recrystallized from ethyl acetate to give 2.60 g of 4-(2-Methyl-1-imidazolyl)-2,2-diphenylbutyronitrile hydrochloride as a colorless powder. Yield: 77 %.
Step b: 4-(2-Methyl-1-imidazolyl)-2,2-diphenylbutyronitrile (7.83 g, 26.0 mmol) and 70 % sulfuric acid (50 ml) were mixed and stirred for 40 minutes at 140 to 150 °C. The solution was made alkaline and extracted with a mixed solvent (5:1) of chloroform with ethanol. The organic extract was dried over anhydrous sodium sulfate and then concentrated. The residue was recrystallized from ethyl acetate-ethanol to give 2.02 g of 4-(2-Methyl-1-imidazolyl)-2,2-diphenylbutylamide as colorless needle-like crystals. Yield: 32 %, Melting point: 189 - 190 °C
Activity:
Imidafenacin (KRP-197/ONO-8025) is the latest antimuscarinic (AM) developed for the treatment of overactive bladder syndrome (OAB) and, at the moment, it is marketed only in Japan. This compound has been developed to improve the tolerability of AM therapy by binding specifically the M3 receptor subtype, thus limiting undesirable adverse events (AEs). Imidafenacin is an AM drug with excellent efficacy, tolerability, and safety. It is indicated for patients with nocturia, nocturnal polyuria, and benign prostatic hyperplasia. This compound, due to its pharmacokinetic properties, gives the opportunity to be easily adjusted in its dosages. Further studies should assess the pharmacokinetics, clinical efficacy, safety, and tolerability of imidafenacin in Caucasian and African populations because this AM agent, at the moment, has been evaluated just in Asian populations. More studies should evaluate and compare efficacy, safety, and tolerability of imidafenacin also with other largely utilized AMs, such as oxybutynin, tolterodine, and fesoterodine, or with the other M3 selective compound, darifenacin [2].
Imidafenacin has been developed for the treatment of overactive bladder as a new anti-cholinergic with high affinities for muscarinic acetylcholine M3 and M1 receptors. The pharmacological profiles of imidafenacin on the urinary bladder function by determining carbamylcholine (CCh)-induced decrease in bladder capacity and distention-induced rhythmic bladder contraction in conscious rats were investigated. In addition, effects of imidafenacin on CCh-induced salivary secretion and performance in the Morris water maze task in rats were investigated to evaluate side effects, such as dry mouth and cognitive dysfunction in the central nervous system (CNS). Imidafenacin prevented the CCh-induced decrease in bladder capacity dose-dependently with an ID50 of 0.055 mg/kg. The results suggest that imidafenacin inhibits urinary bladder contraction to a greater extent than the salivary secretion (compared with the M3 receptor selective antagonist, darifenacin, and the non-selective antagonists, propiverine, tolterodine and oxybutynin) or the CNS functions, such as performance in the Morris water maze task (compared with oxybutynin). In conclusion, imidafenacin has organ selectivity for the bladder over the salivary gland, without influence on the central nervous system such as spatial learning and memory [3].
Imidafenacin (KRP-197/ONO-8025) is the latest antimuscarinic (AM) developed for the treatment of overactive bladder syndrome (OAB) and, at the moment, it is marketed only in Japan. This compound has been developed to improve the tolerability of AM therapy by binding specifically the M3 receptor subtype, thus limiting undesirable adverse events (AEs). Imidafenacin is an AM drug with excellent efficacy, tolerability, and safety. It is indicated for patients with nocturia, nocturnal polyuria, and benign prostatic hyperplasia. This compound, due to its pharmacokinetic properties, gives the opportunity to be easily adjusted in its dosages. Further studies should assess the pharmacokinetics, clinical efficacy, safety, and tolerability of imidafenacin in Caucasian and African populations because this AM agent, at the moment, has been evaluated just in Asian populations. More studies should evaluate and compare efficacy, safety, and tolerability of imidafenacin also with other largely utilized AMs, such as oxybutynin, tolterodine, and fesoterodine, or with the other M3 selective compound, darifenacin [2].
Imidafenacin has been developed for the treatment of overactive bladder as a new anti-cholinergic with high affinities for muscarinic acetylcholine M3 and M1 receptors. The pharmacological profiles of imidafenacin on the urinary bladder function by determining carbamylcholine (CCh)-induced decrease in bladder capacity and distention-induced rhythmic bladder contraction in conscious rats were investigated. In addition, effects of imidafenacin on CCh-induced salivary secretion and performance in the Morris water maze task in rats were investigated to evaluate side effects, such as dry mouth and cognitive dysfunction in the central nervous system (CNS). Imidafenacin prevented the CCh-induced decrease in bladder capacity dose-dependently with an ID50 of 0.055 mg/kg. The results suggest that imidafenacin inhibits urinary bladder contraction to a greater extent than the salivary secretion (compared with the M3 receptor selective antagonist, darifenacin, and the non-selective antagonists, propiverine, tolterodine and oxybutynin) or the CNS functions, such as performance in the Morris water maze task (compared with oxybutynin). In conclusion, imidafenacin has organ selectivity for the bladder over the salivary gland, without influence on the central nervous system such as spatial learning and memory [3].
References:
1. Miyachi, H.; et. al. Synthesis and antimuscarinic activity of a series of 4-(1-Imidazolyl)-2,2-diphenylbutyramides: discovery of potent and subtype-selective antimuscarinic agents. Bioorg Med Chem 1999, 7(6), 1151-1161.
2. Leone, R. M. U.; et. al. Imidafenacin for the treatment of overactive bladder. Expert Opin Pharmacother 2013, 14(10), 1383-1397.
3. Kobayashi, F.; et. al. Pharmacological effects of imidafenacin (KRP-197/ONO-8025), a new bladder selective anti-cholinergic agent, in rats. Comparison of effects on urinary bladder capacity and contraction, salivary secretion and performance in the Morris water maze task. Arzneimittelforschung 2007, 57(3), 147-154.
4. Miyachi, H.; et. al. Novel imidazole derivative and process for producing the same. EP0733621A1
2. Leone, R. M. U.; et. al. Imidafenacin for the treatment of overactive bladder. Expert Opin Pharmacother 2013, 14(10), 1383-1397.
3. Kobayashi, F.; et. al. Pharmacological effects of imidafenacin (KRP-197/ONO-8025), a new bladder selective anti-cholinergic agent, in rats. Comparison of effects on urinary bladder capacity and contraction, salivary secretion and performance in the Morris water maze task. Arzneimittelforschung 2007, 57(3), 147-154.
4. Miyachi, H.; et. al. Novel imidazole derivative and process for producing the same. EP0733621A1
