M3 receptor ( Ki = 0.3 nM ); M3 receptor ( Kd = 0.317 nM ); M2 receptor ( IC50 = 4.13 nM )
Muscarinic acetylcholine receptor M3 subtype (M3; Kb = 0.31 nM)
Muscarinic acetylcholine receptor M2 subtype (M2; Kb = 4.13 nM)
Muscarinic acetylcholine receptor M1 subtype (M1; Kb = 0.55 nM)[1]

KRP-197 demonstrated potent antagonistic activity at the muscarinic M3 receptor in isolated guinea pig ileum (smooth muscle) with a Kb of 0.31 nM. It was approximately 13-fold selective for the M3 receptor over the M2 receptor (atrial muscle, Kb = 4.13 nM) and showed nearly equipotent activity at the M1 receptor (rabbit vas deferens, Kb = 0.55 nM). Its M3 potency was superior to that of terodiline and comparable to or slightly better than oxybutynin in the same assays.[1]

In conscious rats, intraduodenal (i.d.) administration of KRP-197 dose-dependently inhibited isovolumetric bladder contraction (a model of bladder overactivity) with an ED50 of 0.11 mg/kg. This effect was about 19 times more potent than that of oxybutynin-HCl (ED50 = 2.1 mg/kg, i.d.).[1]
Oral (intragastric, i.g.) administration of KRP-197 prevented the decrease in bladder capacity induced by carbachol (a model of detrusor hyperreflexia) with an ED50 of 0.074 mg/kg, which was about 15 times more potent than oxybutynin-HCl (ED50 = 1.1 mg/kg, i.g.).[1]
KRP-197 showed a favorable selectivity profile in rats. The rank order of potency (ED50, i.d.) for inhibiting muscarinic-mediated responses was: urinary bladder (0.11 mg/kg) > gut (0.39 mg/kg) > heart (1.0 mg/kg) and salivary gland (1.1 mg/kg) > eye (pupil diameter, 1.8 mg/kg).[1]
The selectivity ratio for bladder over salivary gland (ED50 for salivation / ED50 for bladder contraction) was 15 for KRP-197, compared to 3.3 for oxybutynin-HCl, indicating superior bladder selectivity.[1]

The antagonistic activities at M1, M2, and M3 muscarinic receptor subtypes were determined using functional isolated tissue assays. M1 receptor activity was assessed by the ability of test compounds to reverse the inhibitory effect of the selective M1 agonist McN-A-343 on electrically stimulated contractions of isolated rabbit vas deferens.[1]
M2 receptor activity was determined by the ability to decrease the effect of acetylcholine in inhibiting the contraction of isolated guinea pig right atria.[1]
M3 receptor activity was evaluated by measuring the decrease in the response of guinea pig ileum muscle strips to acetylcholine. Potency for each subtype was expressed as an affinity constant (Kb), calculated as the molar concentration of the test compound that causes a twofold increase in the EC50 of the agonist.[1]

For evaluating the inhibitory effect on isovolumetric bladder contraction in conscious rats, KRP-197 or oxybutynin-HCl was administered intraduodenally. The dose required to inhibit the contraction by 30% (ED30) or 50% (ED50) was determined.[1]
For the carbachol-induced detrusor hyperreflexia (decreased bladder capacity) model, KRP-197 or oxybutynin-HCl was administered intragastrically (orally) prior to carbachol challenge, and the ED50 for prevention was calculated.[1]
To assess effects on other organs, KRP-197 was administered intraduodenally to rats. Its effects were evaluated on: 1) vagal-induced bradycardia (heart), 2) spontaneous ileal contraction (gut), 3) carbachol-induced salivary secretion (salivary gland), and 4) tonic contraction of the iris sphincter (measured as pupil diameter, eye). The ED50 values for inhibiting these responses were determined.[1]

Absorption, Distribution and Excretion
The absolute oral bioavailability is 57.8%. The time to peak concentration (Tmax) is 1–3 hours after administration. 10% is excreted unchanged in the urine. It is largely eliminated through metabolism, which is believed to be mediated by CYP3A4 and UGT1A4. The estimated volume of distribution is 43.9 L. The estimated clearance is 21.2 L/h. Metabolites/Metabolites It is believed to be metabolized by CYP3A4 and UGT1A4. No active metabolites were observed. Biological Half-Life The elimination half-life is 3 hours. Compared to other anticholinergic drugs such as oxybutynin and tolterodine, midafenadine has lower brain permeability, as indicated by positron emission tomography and radioreceptor assays. Its log D value is 1.5 and its topological polar surface area (tPSA) is 60.91 Ų, indicating that it has low lipid solubility and high polarity, which may be the reason for its low brain permeability. [2]

Protein Binding
Imidafenacin is 88% bound to human plasma proteins. It binds to serum albumin and α1-acid glycoprotein.

[1]. 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 Jun;7(6):1151-61.

[2]. Imidafenacin has no influence on learning in nucleus basalis of Meynert-lesioned rats. Naunyn Schmiedebergs Arch Pharmacol. 2013 Dec;386(12):1095-102.

Imidafenacin is a diarylmethane compound. Imidafenacin is an antispasmodic drug with anticholinergic effects. It reduces urination frequency by antagonizing muscarinic receptors in the bladder and is used to treat overactive bladder. In Japan, it is marketed by Ono Pharmaceutical Co., Ltd. under the brand name Staybla and by Kyoto Pharmaceutical Co., Ltd. under the brand name Uritos. Indications: For the treatment of overactive bladder. FDA Label: Mechanism of Action: Imidafenacin binds to and antagonizes muscarinic M1 and M3 receptors with high affinity. It also antagonizes muscarinic M2 receptors, but with lower affinity. M3 receptors stimulate detrusor muscle contraction by releasing calcium ions through the sarcoplasmic reticulum. M2 receptors are also present in the detrusor muscle, but their function is to inhibit adenylate cyclase, thereby attenuating β-adrenergic receptor-mediated relaxation. In addition, M1 receptors are present on parasympathetic neurons that release acetylcholine in the bladder. They form an autocrine positive feedback loop that further increases acetylcholine release. Imidafenacinin antagonizes these receptors, preventing bladder detrusor muscle contraction, inhibiting the inhibitory effect caused by sympathetic tone, and reducing acetylcholine release. These effects collectively reduce voiding frequency.

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Pharmacodynamics
Imidafenacinin is an antimuscarinic drug that reduces voiding frequency in patients with overactive bladder.

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Imidafenacinin (KRP-197) is a potent and selective muscarinic M3 receptor antagonist developed from a series of 4-(1-imidazolyl)-2,2-diphenylbutyramide derivatives. It is considered a candidate drug for treating bladder dysfunction, such as urinary incontinence associated with overactive bladder. Its mechanism of action is to block M3 receptors on bladder smooth muscle, thereby reducing involuntary contractions. The compound showed good in vivo efficacy in a rat model of bladder dysfunction, exhibiting higher potency than the standard drug hydroxybutyrine and better selectivity for the bladder than for the salivary glands, suggesting that it may reduce side effects such as dry mouth. [1]
As of the time of this publication, a Phase I clinical trial of KRP-197 is underway. [1]

C20H21N3O

319.40024

319.168

C, 75.21; H, 6.63; N, 13.16; O, 5.01

170105-16-5

170105-16-5; 893421-54-0 (Imidafenacin HCl)

6433090

White to off-white solid powder

1.1±0.1 g/cm3

579.7±50.0 °C at 760 mmHg

304.4±30.1 °C

0.0±1.6 mmHg at 25°C

1.603

2.42

1

2

6

24

395

0

NC(C(C1=CC=CC=C1)(C2=CC=CC=C2)CCN3C(C)=NC=C3)=O

SQKXYSGRELMAAU-UHFFFAOYSA-N

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)

4-(2-methylimidazol-1-yl)-2,2-diphenylbutanamide

KRP-197; ONO-8025; KRP 197; ONO 8025; KRP197; ONO8025

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 31.3~63 mg/mL (97.8~197.2 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.51 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (6.51 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (6.51 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)