Agents for the Treatment of Overactive Detrusor. III. Synthesis and Structure-Activity Relationships of N-(4-Amino-2-butynyl)acetamide Derivatives.

Take, Kazuhiko; Okumura, Kazuo; Tsubaki, Kazunori; Terai, Takao; Shiokawa, Youichi

doi:10.1248/cpb.40.1415

Cited by 4 publications

(6 citation statements)

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“…The novel compounds 9–17 were prepared following the procedure depicted in Scheme 2 and were obtained as racemates. The opening of oxiranes 39 , 36 21 , 33 22, and 23 ( 34 ) with allyl alcohol in the presence of perchloric acid yielded compounds 40 , 42 , 43, and 44 , respectively. The olefine 41 was prepared starting from 3,3-diphenylpropane-1,2-diol ( 45 ), 37 whose primary hydroxyl group was selectively protected with tert -butyldimethylsilyl chloride (TBDMSCl) to give compound 46 , which was treated with allyl bromide in the presence of NaH affording olefine 47 .…”

Section: Results and Discussionmentioning

confidence: 99%

Novel Potent Muscarinic Receptor Antagonists: Investigation on the Nature of Lipophilic Substituents in the 5- and/or 6-Positions of the 1,4-Dioxane Nucleus

et al. 2020

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A series of novel 1,4-dioxane analogues of the muscarinic acetylcholine receptor (mAChR) antagonist 2 was synthesized and studied for their affinity at M 1 –M 5 mAChRs. The 6-cyclohexyl-6-phenyl derivative 3b , with a cis configuration between the CH 2 N + (CH 3 ) 3 chain in the 2-position and the cyclohexyl moiety in the 6-position, showed p K i values for mAChRs higher than those of 2 and a selectivity profile analogous to that of the clinically approved drug oxybutynin. The study of the enantiomers of 3b and the corresponding tertiary amine 33b revealed that the eutomers are (2 S ,6 S )-(−)- 3b and (2 S ,6 S )-(−)- 33b , respectively. Docking simulations on the M 3 mAChR-resolved structure rationalized the experimental observations. The quaternary ammonium function, which should prevent the crossing of the blood–brain barrier, and the high M 3 /M 2 selectivity, which might limit cardiovascular side effects, make 3b a valuable starting point for the design of novel antagonists potentially useful in peripheral diseases in which M 3 receptors are involved.

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Section: Results and Discussionmentioning

confidence: 99%

Novel Potent Muscarinic Receptor Antagonists: Investigation on the Nature of Lipophilic Substituents in the 5- and/or 6-Positions of the 1,4-Dioxane Nucleus

et al. 2020

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“…The 2R,4fi-isomer (10) was shown to be the second strongest, albeit with 3 times less activity. The isomers having an S configuration at the 4-position, however, exhibited dramatic attenuation of the activity, being 2 and 3 orders of magnitude less potent in 2S,4Sisomer (11) and 2R,4S-isomer (12), respectively. From these results, it is likely that the configuration of the 4-position plays a critical role in exerting biological activity rather than that of the 2-position, although the preferred configurations are R at the 4-position and S at the 2-position.…”

Section: Pharmacological Resultsmentioning

confidence: 98%

“…Anal. (12). A hot solution of 9 (13.4 g, 45.1 mmol) and (-) -dibenzoyl-L-tartaric acid (17.0g,45.1 mmol) in a mixed solvent of isopropyl alcohol (180 mL) and water (30 mL) was allowed to stand at room temperature overnight.…”

Section: -(Dimethyiamino)-2-phenyl-2-(2-pyridyl)pentane-mentioning

confidence: 99%

“…The corresponding (+)-enantiomer 11 was isolated from the mother liquor as a salt of (+)-dibenzolyl-D-tartaric acid. Recrystallization of the (-)-dibenzoyl-L-tartrate of 9 afforded (+)-enantiomer 12 as a crystalline salt, while (-)-enantiomer 13 was obtained from the mother liquor. The enantiomeric purities of these compounds were assessed by HPLC analyses using a chiral column and were >99% ee.…”

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confidence: 99%

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Synthesis and Anticholinergic Activity of the Four Stereoisomers of 4-(Dimethylamino)-2-phenyl-2-(2-pyridyl)pentanamide

Oyasu¹,

Nagano²,

Akahane³

et al. 1994

J. Med. Chem.

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The four stereoisomers of 4-(dimethylamino)-2-phenyl-(2-pyridyl)pentanamide were synthesized, and the absolute configurations were determined by X-ray crystallography. Pharmacological testing for anticholinergic activity revealed great differences in potency among 10 (2R,4R,IC50 = 0.40 microM), 11 (2S,4S,31 microM), 12 (2R,4S,170 microM), and 13 (2S,4R,0.13 microM). A new drug application for the racemate 8 (FK176, vamicamide) has been filed in Japan for the treatment of overactive detrusor syndrome.

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“…Muscarinic receptor (MR) antagonists are the recommended pharmacotherapy for treating OAB [16,17]. Fesoterodine is a novel antimuscarinic drug, recently approved for the treatment of this disorder [18].…”

Section: Introductionmentioning

confidence: 99%

Urodynamic evaluation of fesoterodine metabolite, doxazosin and their combination in a rat model of partial urethral obstruction

et al. 2010

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(5-HMT, the active metabolite of fesoterodine, previously known as SPM 7605), doxazosin or a combination of both, was given intravenously (0.1 mg/kg body weight), and cystometry was continued for another 45 min. Fifteen healthy, agematched rats served as a control. RESULTSAt 2 weeks after surgery the obstructed rats had an greater bladder weight, threshold pressure (TP) and micturition frequency (MF), and lower bladder capacity (BCap) and micturition volume (MV) than the controls. 5-HMT did not cause urinary retention in obstructed rats, but decreased TP, maximum pressure (MP), spontaneous bladder activity (SA) and, paradoxically, increased MF. Doxazosin alone decreased TP, MP, MF and increased BCap and MV. 5-HMT and doxazosin together did not depress the ability to empty the bladder, and showed decreased TP, MP and SA. CONCLUSIONS5-HMT, alone and in combination, did not impair the voiding ability in obstructed rats. Doxazosin counteracted some of the 'negative' effects of 5-HMT in this model (increase of MF) and did not attenuate the 'positive' effects (decrease of bladder SA). In this model, the combination of 5-HMT and doxazosin appeared to be urodynamically safe and well tolerated.

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Agents for the Treatment of Overactive Detrusor. III. Synthesis and Structure-Activity Relationships of N-(4-Amino-2-butynyl)acetamide Derivatives.

Cited by 4 publications

References 0 publications

Novel Potent Muscarinic Receptor Antagonists: Investigation on the Nature of Lipophilic Substituents in the 5- and/or 6-Positions of the 1,4-Dioxane Nucleus

Novel Potent Muscarinic Receptor Antagonists: Investigation on the Nature of Lipophilic Substituents in the 5- and/or 6-Positions of the 1,4-Dioxane Nucleus

Synthesis and Anticholinergic Activity of the Four Stereoisomers of 4-(Dimethylamino)-2-phenyl-2-(2-pyridyl)pentanamide

Urodynamic evaluation of fesoterodine metabolite, doxazosin and their combination in a rat model of partial urethral obstruction

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