A Potent, Long-Acting, Orally Active (2R)-2-[(1R)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetamide:  A Novel Muscarinic M₃ Receptor Antagonist with High Selectivity for M₃ over M₂ Receptors

Abstract

A novel series of (2R)-2-[(1R)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamides was designed and synthesized based on the structure and biological profiles of an active metabolite 2 of our prototype muscarinic M(3) receptor selective antagonist 1, to develop a potent, long-acting, orally active M(3) antagonist for the treatment of urinary tract disorders, irritable bowel syndrome, and respiratory disorders. Investigation of (2R)-2-[(1R)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamides containing a phenyl or heterocyclic ring as the piperidinyl side chain in place of the 4-methyl-3-pentenyl moiety of 15a revealed that this acid moiety was a versatile template for improving the selectivity for M(3) over M(2) receptors in comparison with the corresponding cyclopentylphenylacetic acid group. However, since the in vitro metabolic stability of these analogues was insufficient compared with that of 2, further derivatization was performed by introducing an appropriate hydrophilic group into the phenyl or 2-pyridyl ring. Thus, the 1-(6-aminopyridin-2-ylmethyl)piperidine analogue 15y exhibiting 190-fold selectivity for M(3) receptors (K(i) = 2.8 nM) over M(2) receptors (K(i) = 530 nM) in a human binding assay and good in vitro metabolic stability in dog and human hepatic microsomes was identified. This compound has excellent oral activity at 4 h after oral dosing (1 mg/kg), inhibiting methacholine-induced bronchoconstriction in dogs, and may be useful in clinical situations in which M(3) over M(2) selectivity is desirable.

Synthesis and Antiproliferative Activitiy of Novel Diaryl Ureas Possessing a 4H‐Pyrido[1,2‐a]pyrimidin‐4‐one Group

“…The commercially available 4-methylpyridin-2-amine in polyphosphate was cyclizated with ethyl 4-chloro-3-oxobutanoate at 1258C to provide compound 1 as a grey solid [6], which was then reacted with 4-nitrophenol in the presence of K 2 CO 3 in DMF to afford 2 [7]. Subsequently, the intermediate 2 underwent reduction with Fe in ethanol to produce compound 3 [8]. The target compounds 4a -4f were synthesized from 3 with a variety of substituted arylisocyanates [9].…”

Discovery of 2-Aminothiazole-4-carboxamides, a Novel Class of Muscarinic M3 Selective Antagonists, through Solution-Phase Parallel Synthesis

“…Coupling of the acid (5) with 10 was achieved using a standard protocol (EDCI and HOBT) to give an amide (6). Deprotection of the Boc group in 6 under acidic conditions, followed by reductive alkylation by treatment with an aldehyde (13) 16) in the presence of NaBH(OAc) 3 afforded 3f in 76% yield.…”

“…M 1 receptors, localized to the post-ganglionic cholinergic nerve terminals and glands, facilitate neurotransmission and gastric secretion. Neuronal M 2 receptors provide a functional negative feedback modulation of acetylcholine (ACh) release.9,10) Extensive efforts have been directed to the identification of potent and subtype-selective M 3 antagonists to complete the classification of the receptor subtypes and to provide more ideal therapeutic agents, [11][12][13] however, few structure classes with sufficient M 3 selectivity have been discovered to date. …”

“…9,10) Extensive efforts have been directed to the identification of potent and subtype-selective M 3 antagonists to complete the classification of the receptor subtypes and to provide more ideal therapeutic agents, [11][12][13] however, few structure classes with sufficient M 3 selectivity have been discovered to date.…”

“…14) As a part of our program for developing a muscarinic M 3 receptor antagonist for the treatment of pulmonary or urinary diseases, we pursued M 3 antagonists that are structurally distinct from a series of 2-(4,4-difluorocyclopentyl)-2-phenylacetamide derivatives such as Compound A 13) and have selectivity for M 3 receptors two orders of magnitude greater than those for M 1 and M 2 receptors. As a result of screening of our in-house chemical collection, a thiazole-4-carboxamide derivative (1) was identified as a new lead structure.…”