Vibegron shows high selectivity and potent agonist activity for ß3-adrenoceptors, irrespective of receptor density.

ß3-Adrenoceptor (AR) agonists are used to treat patients with an overactive bladder (OAB). Clinical proof-of-concept data have been obtained for the ß3-AR agonists vibegron, mirabegron, solabegron, and ritobegron; however, the selectivities of these agents have not been compared directly under the same experimental conditions. Moreover, the bladders of some patients express lower ß3-AR densities than those of healthy individuals, and the ß3-AR density might be expected to affect agonist activity. This study assessed the ß3-AR selectivities of four ß3-AR agonists and examined the effects of ß-AR density on their pharmacological profiles. Functional cellular assays were performed using Chinese hamster ovary-K1 cells expressing three human ß-AR subtypes transfected with different amounts of plasmid DNA (0.1, 0.05, 0.025 µg/well). The half-maximal effective concentration values, intrinsic activities (IAs), and ß3-AR selectivities of vibegron, mirabegron, solabegron, and ritobegron were calculated to assess their pharmacological profiles. The ß3-AR selectivities of vibegron, mirabegron, solabegron, and ritobegron were >7937-, 517-, 21.3-, and >124-fold higher than for ß1-ARs, and >7937-, 496-, >362- and 28.1-fold higher than for ß2-ARs, respectively, under the same experimental conditions. The IAs of mirabegron, solabegron, and ritobegron decreased in line with decreasing receptor density, while the IA of vibegron was maintained at the same level as that of the full agonist isoproterenol at various ß3-AR densities. Vibegron has high ß3-AR selectivity and exhibits full agonist activity, regardless of the ß3-AR density. These results suggest that vibegron is a highly effective and safe drug for treating OAB.

[Pharmacological and clinical profiles of avacopan (TAVNEOS® capsule), a selective C5a receptor antagonist].

Avacopan (TAVNEOS® capsules) is an orally available selective C5a receptor (C5aR) antagonist. It has been approved in Japan since 2021 for the treatment of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), the two major subtypes of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current standard therapy combining glucocorticoids (GC) and immunosuppressants has greatly improved the prognosis of AAV, however, issues such as side effects associated with GC use remain to be resolved. Avacopan suppresses priming of neutrophils induced by the complement component C5a, a process deeply involved in the pathogenesis of AAV. In pre-clinical studies, avacopan inhibited chemotaxis and priming of neutrophils induced by C5a-C5aR signaling. It also significantly suppressed nephritis and renal damage in an ANCA-induced glomerulonephritis mouse model. In the global phase 3 study "ADVOCATE", avacopan achieved both primary endpoints being 1) non-inferior to prednisone in inducing remission at week 26 and 2) superior in sustained remission at week 52 for MPA and GPA patients. Additionally, with avacopan, GC toxicity score was significantly lower and fewer adverse events possibly related to GC were observed. Furthermore, avacopan increased estimated glomerular filtration rate (eGFR) more than prednisone indicating improved renal function. Thus, the novel mechanism of avacopan targeting the complement system is a promising new therapeutic option for AAV with fewer GC-related side effects and better improvement of renal function.

Vibegron inhibits enhanced spontaneous contractions induced by anoxia/reoxygenation in isolated whole bladder from rats.

It has been recently proposed that repeated bladder ischemia/reperfusion induced by chronic pelvic ischemia may lead to detrusor overactivity, followed by lower urinary tract symptoms. Vibegron is a selective ß3-adrenoceptor agonist approved for the treatment of overactive bladder. Several studies have tested ß3-adrenoceptor agonists using animal models with detrusor overactivity related to bladder ischemia/reperfusion. However, whether ß3-adrenoceptor agonists directly affect ischemia/reperfusion-evoked detrusor overactivity is unclear. Therefore, we examined whether bladder anoxia/reoxygenation could enhance spontaneous bladder contractions (SBCs) and investigated the effect of vibegron on enhanced SBCs. Isolated whole bladders from rats were incubated with Krebs solution aerated with 95% N2 + 5% CO2 for 5 h (anoxia). Subsequently, the bathing solution was replaced with an oxygen-saturated solution (reoxygenation). Anoxia/reoxygenation caused enhancement of the amplitude but not the frequency of SBC compared with that before reoxygenation. Vibegron (0.3-30 µM) inhibited this increase in SBC amplitude, but not the frequency, in a dose-dependent manner. The inhibitory effect of vibegron was not affected by pretreatment with the adenylyl cyclase inhibitor SQ22536 (100 µM) or protein kinase A inhibitor KT5720 (1 µM) and was not accompanied by considerable changes in cyclic adenosine monophosphate (cAMP) content in the bladder. In contrast, the large conductance potassium channel inhibitor iberiotoxin (100 nM) suppressed the inhibitory effect of vibegron. These results suggest that bladder ischemia/reperfusion induces SBC enhancement and vibegron directly inhibits detrusor overactivity via the large conductance potassium channel, which involves ß3-adrenoceptor, rather than the cAMP signaling pathway.

Effects of vibegron, a novel ß3-adrenoceptor agonist, and its combination with imidafenacin or silodosin in a rat with partial bladder outlet obstruction.

Urgency is regarded as a core symptom of overactive bladder (OAB) and may correspond to detrusor overactivity (DO). One of the causes of OAB in men is bladder outlet obstruction (BOO) associated with benign prostatic hyperplasia (BPH). Vibegron is a novel selective ß3-adrenoceptor agonist recently approved for the treatment of OAB. However, in OAB patients with BPH (BPH/OAB), the effects of vibegron on storage functions, especially DO and voiding functions have not been fully investigated. In this study, we evaluated the effects of a single administration of vibegron on storage function (particularly focusing on non-voiding contractions [NVC] considered a surrogate marker for DO) and voiding functions, using a rat model of partial BOO as a model for BPH/OAB. Furthermore, the utility of vibegron in combination with imidafenacin (an antimuscarinic) or silodosin (an α1A-adrenoceptor blocker) was evaluated. Six weeks after establishment of BOO, the frequency and amplitude of NVC, evaluated by cystometrography, increased. Vibegron inhibited the frequency of NVC without affecting voiding function (micturition pressure, residual volume, and voiding efficiency). Imidafenacin and silodosin also inhibited the frequency of NVC; however, the inhibitory effects of vibegron were stronger than those of imidafenacin or silodosin. The combination of vibegron with imidafenacin or silodosin additively inhibited the frequency of NVC without worsening the voiding function. These results suggest the possibility that vibegron is effective as a single agent for the amelioration of storage symptoms in BPH/OAB patients and is useful in combination with either antimuscarinics or α1-adrenoceptor blockers.

Effects of the combination of vibegron and imidafenacin on bladder function in urethane-anesthetized rats.

The combination of a ß3-adrenoceptor agonist and an antimuscarinic agent was revealed to be more effective than monotherapy for patients with overactive bladder and in animal models. However, its influence on voiding functions has not been well documented. Therefore, during intermittent-cystometry, we studied the effects of vibegron (a novel ß3-adrenoceptor agonist) and imidafenacin (an antimuscarinic agent) alone to determine their dose levels for the combination study. Then, the effects of the combination on voiding functions were investigated in urethane-anesthetized rats (1.0 g/kg s.c.). Independently, vibegron (0.3-3 mg/kg, i.v.) and imidafenacin (0.001 and 0.003 mg/kg, i.v.) dose-dependently increased bladder capacity and voided volume, without affecting voiding functions such as residual volume, voiding efficiency, and micturition pressure. However, vibegron also increased bladder compliance. The combination of vibegron (3 mg/kg) and imidafenacin (0.003 mg/kg) significantly increased bladder capacity and voided volume when compared to those with monotherapy using each individually. The combination did not change residual volume, voiding efficiency, and micturition pressure, compared to those in the vehicle group. We identified no responses in resiniferatoxin (RTX)-treated rats, as opposed to those identified after administering vibegron (3 mg/kg), imidafenacin (0.003 mg/kg), or both to non-RTX-treated rats. These outcomes might have resulted from the combination of the increased effect of vibegron on bladder compliance and the inhibitory effect of both vibegron and imidafenacin on the activation of bladder afferent nerves.

Silodosin, an α(1A)-Adrenoceptor Antagonist, May Ameliorate Ischemia-Induced Bladder Denervation and Detrusor Dysfunction by Improving Bladder Blood Flow.

BACKGROUND/AIMS: This study was performed to investigate the detailed mechanism underlying the effects of the selective α(1A)-adrenoceptor antagonist, silodosin, on bladder function in a rat model of atherosclerosis-induced chronic bladder ischemia (CBI). METHODS: The CBI model was prepared by balloon endothelial injury of the bilateral iliac arteries in male rats. Using an osmotic pump, the CBI rats received either silodosin or vehicle alone subcutaneously for 8 weeks. Rats received a 2% cholesterol diet throughout the experiment. Bladder blood flow (BBF) was measured. Immunohistochemical staining was performed to determine the nerve distribution and nerve growth factor expression in the bladder. Bladders were used for muscle strip contraction analysis. The expression levels of muscarinic M2 and M3 receptors were measured. RESULTS: Silodosin abrogated the decrease in BBF in CBI rats. Silodosin prevented the decrease in nerve distribution and increase in nerve growth factor expression in the CBI model. Bladder contractile response was reduced in the CBI group. Silodosin ameliorated the effect on the bladder contractile response. The level of muscarinic M3 receptor mRNA present in the bladder of CBI rats was increased by silodosin. CONCLUSION: The results of this study suggest that silodosin ameliorates the denervation of the bladder and effects on detrusor contractile function under ischemic conditions by restoring BBF.

Bladder selectivity of the novel ß3-agonist ritobegron (KUC-7483) explored by in vitro and in vivo studies in the rat.

We performed in vitro and in vivo experiments to evaluate the pharmacological profile of ritobegron and its effects on the bladder in rats. ß(3)-AR selectivity was assessed using CHO cells expressing various subtypes of the human ß-adrenoceptor (AR). Effects on isolated organs were evaluated using the organ-bath method. Effects on intravesical pressure, heart rate, and mean blood pressure were evaluated in urethane-anesthetized rats. Ritobegron increased cAMP accumulation in a concentration-dependent manner in CHO cells expressing any one of three human ß-AR, its selectivity for ß(3)-AR being 301-fold and 32-fold higher versus ß(1)-AR and ß(2)-AR, respectively. Ritobegron decreased the resting tension of the isolated bladder in a concentration-dependent manner (EC(50), 7.7 × 10(-8) mol/L; maximal relaxation, 97.0 %), and the ß(3)-AR antagonist SR58894A produced a parallel rightward-shift of this concentration-response curve without altering the maximal response [pK(B) value, 6.43]. Ritobegron concentration-dependently increased atrial rate and decreased myometrial contractions in vitro, and its selectivity for the bladder was 2,078-fold higher versus the atria and 14-fold higher versus the uterus. In vivo, ritobegron induced a dose-dependent decrease in intravesical pressure (ED(50) 0.4 mg/kg), without affecting heart rate and only slightly lowering mean blood pressure. Thus, ritobegron displayed potent and selective ß(3)-AR agonistic activity toward transfected human ß-AR and exhibited a high selectivity for the bladder versus other organs in rats. Moreover, it decreased intravesical pressure with minimal effects on the cardiovascular system in anesthetized rats. These results suggest that ritobegron shows promise as a potential agent for the treatment of overactive bladder.

Effects of ritobegron (KUC-7483), a novel selective ß3-adrenoceptor agonist, on bladder function in cynomolgus monkey.

We evaluated the pharmacological profile of ritobegron [KUC-7483; (-)-ethyl 2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)-2,5-dimethylphenyloxy]acetate monohydrochloride] and its effects on the bladder in cynomolgus monkeys by in vitro and in vivo experiments. In vitro, ritobegron decreased the resting tension of the isolated bladder in a concentration-dependent manner (EC(50) 8.2 ± 2.3 × 10(-7) M; maximal relaxation 88.7 ± 3.7%). The ß(3)-adrenoceptor (AR) antagonist 3-(2-allylphenoxy)-1-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol hydrochloride (SR58894A) produced a rightward shift of this concentration-response curve without altering the maximal response (pK(B) value 6.56 ± 0.35). In isolated atria, ritobegron increased the atrial rate only at high concentrations (EC(50) 6.5 ± 1.2 × 10(-5) M). Ritobegron had no effect on tracheal contraction at concentrations from 10(-9) to 10(-4) M, and even at the highest concentration tested, 10(-3) M, the maximal relaxation it induced was only 26.7 ± 8.1%. Tests of the selectivity of ritobegron for the bladder gave values of 79.3- and 1200-fold higher versus atria and trachea, respectively. In the in vivo study ritobegron significantly decreased intravesical pressure (ED(50) 1.44 mg/kg) without affecting either mean blood pressure or heart rate. In conclusion, ritobegron displayed potent and selective ß(3)-AR agonistic activity and relaxed the monkey isolated bladder, and in vivo it decreased intravesical pressure without affecting cardiovascular parameters. These results suggest that ritobegron may be a promising potential agent for the treatment of overactive bladder.

Effects of ritobegron (KUC-7483), a novel ß3-adrenoceptor agonist, on both rat bladder function following partial bladder outlet obstruction and on rat salivary secretion: a comparison with the effects of tolterodine.

The objective of this study was to investigate the effects of the ß3-adrenoceptor (AR) agonist ritobegron on rat bladder function following partial bladder outlet obstruction and on rat salivary secretion. In addition, the effects of ritobegron were compared with those of the anti-muscarinic agent tolterodine. After a 6-week partial bladder outlet obstruction (BOO), drug effects on bladder functions were evaluated using cystometrography. Effects on carbachol (CCh)-induced salivary secretion were evaluated in urethane-anesthetized rats. Ritobegron significantly decreased the frequency of non-voiding contractions (NVC), while both ritobegron and tolterodine each significantly decreased the amplitude of NVC. Ritobegron had no effect on either the micturition pressure (MP) or the residual volume (RV). In contrast, tolterodine dose-dependently decreased MP and increased RV. Ritobegron had no effect on CCh-induced salivary secretion, whereas tolterodine dose-dependently decreased it. Ritobegron decreased both the frequency and amplitude of NVC, which is similar to its effect on the contractions associated with detrusor overactivity (DO) in patients with an overactive bladder (OAB), without affecting MP, RV, or CCh-induced salivary secretion. Although tolterodine reduced the amplitude of NVC, it also markedly increased RV and significantly inhibited CCh-induced salivary secretion. These results suggest that use of ritobegron, a ß3-AR agonist, is unlikely to lead to the residual urine and dry mouth symptoms that are associated with anti-muscarinic drugs, and that ritobegron may hold promise as a safe and effective agent for OAB treatment.

Uroselectivity in male dogs of silodosin (KMD-3213), a novel drug for the obstructive component of benign prostatic hyperplasia.

AIMS: Our main aim was to compare the prostatic selectivity of silodosin with that of other alpha(1)-adrenoceptor (AR) antagonists. METHODS: We examined uroselectivities in two sets of experiments namely, in vitro and in vivo functional studies using male dogs. In the in vitro study, after evaluating the inhibitory effects of silodosin on noradrenaline (NA)-induced contractions in the isolated prostate and isolated carotid artery using the Magnus method, we calculated prostatic selectivity. In the in vivo study, we examined the effects of drugs on the hypogastric nerve stimulation (HNS)-induced increase in intraurethral pressure (IUP) and on blood pressure. The uroselectivity of silodosin was compared with those of tamsulosin and naftopidil. RESULTS: In vitro, all drugs antagonized NA-induced contraction in both prostate and carotid artery. The prostatic selectivity of silodosin (79.4) was much higher than those of tamsulosin (1.78), naftopidil (0.55), BMY 7378 (0.115), and prazosin (0.01). In vivo, intravenously (i.v.) administered silodosin dose-dependently inhibited the HNS-induced increase in IUP with much less hypotensive effect than either tamsulosin or naftopidil, the uroselectivity (ED(15)/ID(50)) of silodosin (237) being significantly higher than those of tamsulosin (1.21) and naftopidil (2.65). CONCLUSIONS: Our results clearly demonstrate that silodosin is a potent and highly selective alpha(1A)-AR antagonist. A selective alpha(1A)-AR antagonist such as silodosin may have good potential as a less-hypotensive drug for the treatment of urinary dysfunction in benign prostatic hyperplasia patients.

[Effects of silodosin (KMD-3213) on phenylephrine-induced increase in intraurethral pressure and blood pressure in rats--study of the selectivity for lower urinary tract].

The effects of silodosin, an alpha(1A)-adrenoceptor (AR) antagonist, and of other alpha(1)-AR antagonists on the phenylephrine (PE)-induced increase in intraurethral pressure (IUP) and on blood pressure (BP) were studied in anesthetized rats. The drugs were administered intravenously (i.v. study) or intraduodenally (i.d. study). IUP and BP were measured via catheters inserted into the prostatic urethra and common carotid artery, respectively. In the i.v. study, drugs were administered every 30 min for effects on BP, and 5 min before each PE-injection (30 microg/kg, every 60 min) with stepwise increases in dose for effects on IUP. In the i.d. study, one dose of drug was administered per rat, then IUP and BP were observed for 4 h [IUP being measured time-dependently following PE-injection (30 microg/kg)], and IUP and BP were expressed as a percentage of the values without any drugs. ID(50) for IUP and ED(15) for BP were calculated, and uroselectivity was determined as ED(15)/ID(50) for each drug. All drugs both inhibited the IUP increase and lowered BP, each effect being dose-dependent. The order of uroselectivities was silodosin (11.7)>tamuslosin (2.24)>naftopidil (0.133) in the i.v. study, and silodosin (26.0)>tamuslosin (3.82)>naftopidil (1.39) in the i.d. study. Selectivity for the lower urinary tract (LUT) was higher for silodosin than for tamsulosin (alpha(1A)/alpha(1D)-AR), naftopidil (alpha(1D)-AR), or prazosin (non-selective alpha(1)-AR). These results suggested that an alpha(1A)-AR selective antagonist like silodosin might be effective in the LUT without causing hypotension.

[Duration of action of silodosin (KMD-3213) against phenylephrine-induced increase in intraurethral pressure in rats].

The duration of action of Silodosin (KMD-3213) against the phenylephrine-induced increase in intraurethral pressure in urethane-anesthetized rats was compared with that of tamsulosin hydrochloride. Silodosin, tamsulosin, or vehicle was orally administered to fasted male rats. Then, under urethane anesthesia, a cannula was inserted into the prostatic urethra. Phenylephrine, at a dose of 30 microg/kg, was infused (infusion rate: 36 ml/h; infusion time: 100 s/kg) via the femoral vein at 12 h, 18 h, or 24 h after administration of the study drug, and the intraurethral pressure in the prostate region was measured. Although the plasma silodosin concentration would have resolved within a few hours, silodosin significantly inhibited the phenylephrine-induced increase in intraurethral pressure (versus the vehicle-treated group) at 12 h, 18 h, and 24 h after its oral administration (at doses of 100 microg/kg and above, 1000 microg/kg and above, and 3000 microg/kg, respectively). On the other hand, tamsulosin hydrochloride showed no inhibitory action at 24 h after its oral administration at doses up to 3000 microg/kg. Thus, silodosin inhibits the phenylephrine-induced increase in intraurethral pressure for a longer time than tamsulosin hydrochloride.

Effects of mitiglinide and sulfonylureas in isolated canine coronary arteries and perfused rat hearts.

Our aim was to compare the cardiovascular effects of mitiglinide ((+)-monocalcium bis[(2S,3a,7a-cis)-alpha-benzylhexahydro-gamma-oxo-2-isoindolinebutyrate] dehydrate), a novel hypoglycemic drug, with those of glibenclamide and glimepiride, two sulfonylurea drugs. In isolated canine coronary arteries (organ-bath method), mitiglinide, glibenclamide, and glimepiride competitively antagonized the cromakalim-induced relaxation (pA2 values, 5.29, 7.36, and 7.49, respectively). In isolated perfused rat hearts (Langendorff method) subjected to a 12-min global ischemia followed by a 30-min reperfusion, mitiglinide (3 x 10(-6) mol/l) altered neither the change in coronary perfusion flow nor the alterations in cardiac functions associated with reperfusion. In contrast, both glibenclamide (3 x 10(-8) mol/l) and glimepiride (1 x 10(-7) mol/l) significantly reduced coronary perfusion flow after reperfusion. Moreover, at 30 min of reperfusion: (1) glibenclamide induced a significant increase in left ventricular end-diastolic pressure and significant decreases in left ventricular systolic pressure, left ventricular developed pressure, and the maximum first derivative of left ventricular pressure, while (2) glimepiride induced significant decreases in left ventricular developed pressure and the maximum first derivative of left ventricular pressure. Thus, the cardiovascular effects of mitiglinide (at least, in these rat and dog preparations) may be weaker than those of glibenclamide and glimepiride.