Antimuscarinic 3-(2-Furanyl)quinuclidin-2-ene Derivatives:  Synthesis and Structure−Activity Relationships

Johansson, Gary; Sundquist, Staffan; Nordvall, Gunnar; Nilsson, Björn M.; Brisander, Magnus; Nilvebrant, Lisbeth; Hacksell, Uli

doi:10.1021/jm970346t

Cited by 24 publications

(34 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The second set, illustrated in Figure 4, consisted of all furan-based quinuclidinene muscarinic antagonists from two structure-activity studies, with the addition of two benzofuran compounds for testing non-additive predictions [20; 21]. The activity range was pK d 5.0–8.0.…”

Section: Methods and Datamentioning

confidence: 99%

See 1 more Smart Citation

QMOD: physically meaningful QSAR

Jain

2010

J Comput Aided Mol Des

View full text Add to dashboard Cite

Computational methods for predicting ligand affinity where no protein structure is known generally take the form of regression analysis based on molecular features that have only a tangential relationship to a protein/ligand binding event. Such methods have utility in retrospective rationalization of activity patterns of substituents on a common scaffold, but are limited when either multiple scaffolds are present or when ligand alignment varies significantly based on structural changes. In addition, such methods generally assume independence and additivity of effect from scaffold substituents. Collectively, these non-physical modeling assumptions sharply limit the utility of widely used QSAR approaches for prospective prediction of ligand activity. The recently introduced Surflex-QMOD approach, by virtue of constructing physical models of binding sites, comes closer to a modeling approach that is congruent with protein ligand binding events. A set of congeneric CDK2 inhibitors showed that induced binding pockets can be quite congruent with the enzyme’s active site but that model predictivity within a chemical series does not necessarily depend on congruence. Muscarinic antagonists were used to show that the QMOD approach is capable of making accurate predictions in cases where highly non-additive structure activity effects exist. The QMOD method offers a means to go beyond non-causative correlations in QSAR analysis.

show abstract

Section: Methods and Datamentioning

confidence: 99%

“…The four muscarinic antagonists shown were synthesized as part of the same effort for developing a treatment for urinary incontinence [20; 21]. While two single changes from the parent compound yielded improvements over a full log unit in K d , the combination of the two changes was worse than either of the singly substituted compounds.…”

Section: Introductionmentioning

confidence: 99%

QMOD: physically meaningful QSAR

Jain

2010

J Comput Aided Mol Des

View full text Add to dashboard Cite

show abstract

“…Some furan-based derivatives are muscarinic antagonists 1 and show inhibitory activity towards cholesterol O-acyltransferase. 2 Mirone 3 summarized the Raman and infrared data for 2FF and reported intense doublets at 2800, 1670, 1420 and 1370 cm 1 .…”

Section: Introductionmentioning

confidence: 99%

Raman spectroscopy, surface‐enhanced Raman spectroscopy and density functional theory studies of 2‐formylfuran

Iliescu

Bolboaca

Pacurariu

et al. 2003

J Raman Spectroscopy

View full text Add to dashboard Cite

The Raman spectrum of 2-formylfuran in the liquid phase shows pairs of bands whose temperature and solvent dependence behavior can be interpreted in terms of cis-trans conformational equilibrium. Density functional theory (DFT) calculations performed at the BPW91/6-311+G * and B3LYP/6-311+G * theoretical levels show that the trans-isomer is more stable than the cis-isomer by 2.81 and 3.12 kJ mol −1 , respectively. The theoretical 1H values obtained at these theoretical levels [2.99 kJ mol −1 (BPW91) and 3.2 kJ mol −1 (B3LYP)] are very close to the experimental value 1H = 2.52 kJ mol −1 determined from the plots of logarithmic relative intensities of the band pairs 1673/1692, 1477/1465 and 1396/1371 cm −1 of these isomers against reciprocal temperature. The surface-enhanced Raman spectrum of 2-formylfuran in silver colloid suggests the chemisorption of this molecular species on the silver surface both through the ring oxygen and the oxygen atom of the substituent group, the cis-form being preferred in the adsorption state. The adsorbed molecules are oriented perpendicular or least tilted with respect to the silver surface.

show abstract

“…Substituted quinuclidines possess interesting and diverse pharmacological activities as the quinuclidine nucleus has been found to be a good mimic for the quaternary nitrogen in acetylcholine [1], The synthetic methods most frequently used for the preparation of quinuclidine-based pharmaceutical lead structures have started from quinuclidin-3-one [2,3]. In the course of our investigations on the synthesis of chiral quinuclidinone analogs the title compound has been prepared from Quincoridine® [4] in enantiopure form following an eight step pathway [5].…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of (1S,2R,4S)-2-bromomethyl-1-azabicyclo[2.2.2]·octan-5-one, C8H12BrNO

Wartchow

Frackenpohl

Hoffmann

2000

Zeitschrift Für Kristallographie - New Crystal Structures

View full text Add to dashboard Cite

C 8 Hi 2 BrNO, orthorhombic, P2\2\2] (No. 19), a = 7.002(1) Ä, b = 7.432(1) Ä, c = 16.762(2) Ä, V=872.3 Ä 3 ,Z = 4, R & (F) = 0.031, wR m (F 2 ) = 0.050, T= 300 K. Source of materialMethanesulfonyl chloride (0.39 ml, 5.0 mmol) was added to (lS,2Ä,4S)-2-hydroxymethyl-l-azabicyclo[2.2.2]octan-5-one (600 mg, 3.9 mmol) and Et3N (1.08 ml, 7.7 mmol) in absolute CH2CI2 (10 ml) at 273 K. The reaction mixture was stirred for 10 h at room temperature, diluted with CH2CI2 and extracted with saturated aqueous NaHC03. The organic layer was dried, the solvent evaporated and the crude product (83 %,748 mg,3.21 mmol) dissolved in abs. dioxan (5 ml). Powdered lithium bromide (838 mg, 9.64 mmol, 3.0 eq) was added and the mixture was refluxed for 24 h at 383 K. After addition of saturated aqueous NaHCC>3 the aqueous layer was extracted with CH2CI2, and the combined organic layer dried (MgSCU) and evaporated. Purification by chromatography (EtOAc / MeOH 20:1) furnished the desired brominated ketone which was recrystallized from MTBE / acetone. Experimental detailsCompleteness of Laue data set in class mmm 100%, but Friedel pairs kept separate in the refinement. The empirical absorption corerection was based on a function of the mean intensity of the imaging plate versus angle φ improving the Rint from 0.201 to 0.076. A spherical absorption correction with μ-r = 0.34 was applied too. The Flack parameter was found to be -0.01(2). DiscussionSubstituted quinuclidines possess interesting and diverse pharmacological activities as the quinuclidine nucleus has been found to be a good mimic for the quaternary nitrogen in acetylcholine [1], The synthetic methods most frequently used for the preparation of quinuclidine-based pharmaceutical lead structures have started from quinuclidin-3-one [2, 3]. In the course of our investigations on the synthesis of chiral quinuclidinone analogs the title compound has been prepared from Quincoridine® [4] in enantiopure form following an eight step pathway [5]. Because of their low molecular weight and their compact azabicyclic structure quincoridine-derivatives are of general interest [6,7]. Oxidative degradation of the vinylic side chain of quincoridine was carried out by double bond shift, 1,2-dihydroxylation and subsequent diol cleavage. O-Mesylation of resulting (15,2/f,4S)-2-hydroxymethyl-l-azabicyclo[2.2.2]octan-5-one followed by LiBr-promoted SN2 displacement furnished the desired γ-amino δ-bromo ketone of which we present the crystal structure. (15,2if,45)-2-Bromomethyl-l-azabicyclo[2.2.2]-octan-5-one contains a prochiral carbonyl group and three stereogenic centres including the chiral 5-configurated bridgehead nitrogen. The analysis of N,C-bond angles shows a less developed pyramidalization of the bridgehead nitrogen than in 10,11-didehydroquincorine and -quincoridine [8,9,10]. Table 1. Data collection and handling. Crystal: Wavelength: μ: Diffractometer, scan mode: 20max: N(hkl)measured, N(hkl)u"ique: Criterion for I 0 bs, N(hkljp;. N(param) rermed: Programs: colourless plate II (100), size 0.06...

show abstract

Antimuscarinic 3-(2-Furanyl)quinuclidin-2-ene Derivatives: Synthesis and Structure−Activity Relationships

Cited by 24 publications

References 46 publications

QMOD: physically meaningful QSAR

QMOD: physically meaningful QSAR

Raman spectroscopy, surface‐enhanced Raman spectroscopy and density functional theory studies of 2‐formylfuran

Crystal structure of (1S,2R,4S)-2-bromomethyl-1-azabicyclo[2.2.2]·octan-5-one, C8H12BrNO

Contact Info

Product

Resources

About