Vol. 297, Issue 2, 790-797, May 2001

Pharmacological Properties of (2R)-N-[1-(6-Aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2- hydroxy-2-phenylacetamide: A Novel Muscarinic Antagonist with M₂-Sparing Antagonistic Activity

Hiroyasu Hirose, Ikuo Aoki, Toshifumi Kimura, Toru Fujikawa, Tomoshige Numazawa, Kaori Sasaki, Akio Sato, Takuro Hasegawa, Masaru Nishikibe, Morihiro Mitsuya, Norikazu Ohtake, Toshiaki Mase and Kazuhito Noguchi

Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Ibaraki, Japan

We evaluated the pharmacological profiles of (2R)-N-[1-(6- aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide(compound A), which is a novel muscarinic receptor antagonist with M₂-sparing antagonistic activity. Compound A inhibited [³H]NMS binding to cloned human muscarinic m1, m2, m3, m4, and m5 receptors expressed in Chinese hamster ovary cells with K_i values (nM) of 1.5, 540, 2.8, 15, and 7.7, respectively. In isolated rat tissues, compound A inhibited carbachol-induced responses with 540-fold selectivity for trachea (K_B = 1.2 nM) over atria (K_B = 650 nM). In in vivo rat assays, compound A inhibited acetylcholine-induced bronchoconstriction and bradycardia with intravenous ED₅₀ values of 0.022 mg/kg and 10 mg/kg, respectively. Furthermore, in dogs, compound A (0.1-1 mg/kg p.o.) dose dependently shifted the methacholine concentration-respiratory resistance curves. In mice, compound A (10 mg/kg i.v.) did not inhibit oxotremorine-induced tremor. The brain/plasma ratio (K_p) of compound A (3 mg/kg i.v.) was 0.13 in rats; this K_p was less than that of scopolamine (1.7) and darifenacin (0.24). The inhibition of compound A (3 mg/kg i.v.) on ex vivo binding in rat cerebral cortex was almost similar to that of NMS. These findings demonstrate that compound A has high selectivity for M₃ receptors over M₂ receptors, displays a potent, oral M₃ antagonistic activity without inhibition of central muscarinic receptors because of low brain penetration. It is well known that central muscarinic antagonists may have diverse CNS effects, and M₂ receptors regulate cardiac pacing and act as autoreceptors in the lung and bladder. Thus, compound A may have fewer cardiac or CNS side effects than nonselective compounds.