Synthesis and antimuscarinic activity of a Series of 4-(1-Imidazolyl)-2,2-diphenylbutyramides: discovery of potent and subtype-selective antimuscarinic agents

Absorption, Metabolism, and Excretion of [14C]Imidafenacin, a New Compound for Treatment of Overactive Bladder, After Oral Administration to Healthy Male Subjects

“…In addition, imidafenacin inhibited carbachol-induced contraction of isolated guinea pig and human bladder mediated by the M 3 receptor and acetylcholine release from isolated rat and human bladder mediated by the prejunctional M 1 receptor (Murakami et al, 2003;Kobayashi et al, 2007a). A carbachol-induced reduction in bladder capacity and distention-induced rhythmic bladder contraction were prevented by imidafenacin dose dependently in conscious rats (Miyachi et al, 1999;Kobayashi et al, 2007b). On the other hand, the effects of imidafenacin on carbachol-induced salivary gland secretion mediated by M 3 receptor alone were less potent than those on bladder contraction in rats (Miyachi et al, 1999;Kobayashi et al, 2007b).…”

“…A carbachol-induced reduction in bladder capacity and distention-induced rhythmic bladder contraction were prevented by imidafenacin dose dependently in conscious rats (Miyachi et al, 1999;Kobayashi et al, 2007b). On the other hand, the effects of imidafenacin on carbachol-induced salivary gland secretion mediated by M 3 receptor alone were less potent than those on bladder contraction in rats (Miyachi et al, 1999;Kobayashi et al, 2007b).In the pharmacokinetic assays in the preclinical toxicology studies, imidafenacin was absorbed rapidly with absolute bioavailability of 5.6% in rats and 36.1% in dogs after oral administration (Masuda et al., unpublished observations). Orally administered [ 14 C]imidafenacin was excreted as many metabolites in the feces, and the total recovery in the urine and feces were more than 95% of the administered dose in rats and dogs (Sato et al, unpublished observations).…”

“…Compounds with high affinity for the muscarinic acetylcholine receptor, including propiverine, tolterodine, oxybutynin, darifenacin, and solifenacin, have been used in management of overactive bladder (Chapple et al, 2002;Andersson and Yoshida, 2003;Andersson, 2004;Robinson and Cardozo, 2005). Imidafenacin showed high in vitro affinity for muscarinic receptor subtypes M 1 and M 3 in the functional assay using isolated animal tissues and in the binding assay using recombinant human receptors (Miyachi et al, 1999;Kobayashi et al, 2007a). In addition, imidafenacin inhibited carbachol-induced contraction of isolated guinea pig and human bladder mediated by the M 3 receptor and acetylcholine release from isolated rat and human bladder mediated by the prejunctional M 1 receptor (Murakami et al, 2003;Kobayashi et al, 2007a).…”

Biomimetic Oxidation of 2-Methylimidazole Derivative with a Chemical Model System for Cytochrome P-450.

“…Based on these observations, we applied this biomimetic oxidation reaction system to 4-(2-methyl-1-imidazolyl)-2,2-diphenyl butyramide [13][14][15][16] (KRP-197; Figure 2), which was developed as a dual antagonist of muscarinic acetylcholine receptors M 1 and M 3 . KRP-197 is a candidate drug for the treatment of urinary incontinence associated with bladder muscle instability, and is currently under clinical study.…”

“…4-(2-Methyl-1-imidazolyl)-2,2-diphenylbutyramide [13][14][15][16] (KRP-197) and its tetradeuterio derivative (D 4 -KRP-197) were synthesized by the Discovery Research Laboratory of Kyorin Pharmaceutical Co. Ltd.…”