2D-QSAR and 3D-QSAR/CoMSIA Studies on a Series of (R)-2-((2-(1H-Indol-2-yl)ethyl)amino)-1-Phenylethan-1-ol with Human β3-Adrenergic Activity (original) (raw)
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Journal of Computer-Aided Molecular Design, 2005
The b 3 -adrenoreceptor (b 3 -AR) has been shown to mediate various pharmacological and physiological effects such as lipolysis, thermogenesis, and intestinal smooth muscle relaxation. It also plays an important role in glucose homeostasis and energy balance. Molecular modeling studies were undertaken to develop predictive pharmacophoric hypothesis and 3D-QSAR model, which may explain variations in b 3 -AR agonistic activity in terms of chemical features and physicochemical properties. The two softwares, CATALYST for pharmacophoric alignment and APEX-3D for 3D-QSAR modeling were used to establish the structure activity relationships for b 3 -AR agonistic activity. Among the several statistically significant models, the selection of the best pharmacophore and 3D-QSAR model was based on its ability to estimate the activity of external test sets of similar and different structural types along with the reasonable consistency of the model with the limited information of the active site of b 3 -AR. The final 3D-QSAR model was derived using the pharmacophoric alignments from the hypothesis which consisted of four chemical features: basic or positive ionizable feature on the nitrogen of the aryloxypropylamino group, two ring aromatic features corresponding to the phenyl ring of the phenoxide and the benzenesulphonamido groups and a hydrogen-bond donor (HBD) in the vicinity of the nitrogen atom of the benzenesulphonamido group with the most active molecule mapping in an energetically favorable extended conformation. This hypothesis was in agreement with the site directed mutagenesis studies on human b 3 -AR and correlated well the observed and estimated activity both in, training and both the external test sets. It also mapped reasonably well to six b 3 -AR agonists of different structural classes under clinical development and thus this hypothesis may have a universal applicability in providing a powerful template for virtual screening and also for designing new chemical entities (NCEs) as b 3 -AR agonists.
Discovery of L-755,507: A subnanomolar human β3 adrenergic receptor agonist
Bioorganic & Medicinal Chemistry Letters, 1998
A study of 4-acylaminobenzenesulfonamides in a cloned human 1~3 adrenergic receptor assay resulted in the discovery of n-hexylurea, L-755,507 (22). This 0.43 nM 1~3 agonist, which is > 440-fold selective over both ~1 and ~2 binding, is among the most potent human ~3 agonists reported to date..© 1998 Elsevier Science Ltd. All rights reserved.
Medicinal Chemistry Research, 2010
Molecular modeling studies were performed to develop a predictive common pharmacophore hypothesis (CPH) and use it for alignment in threedimensional (3D) quantitative structure-activity relationship (QSAR) studies using CoMFA and CoMSIA, with a diverse set of 80 b 3 -adrenergic receptor (b 3 -AR) agonists. Using PHASE (Pharmacophore Alignment and Scoring Engine) six-point CPH with one acceptor, one negative charge, one positive charge, and three rings, features were derived for pharmacophore-based alignment of molecules. CPH was selected by correlating the observed and estimated activity for the training set and test set of molecules using partial least squares analysis. The validated pharmacophore hypothesis was used for alignment of molecules in CoMFA and CoMSIA model development. The models so generated showed a good ''predictive'' r 2 value of 0.6635 and 0.8665 for CoMFA and CoMSIA, respectively. The 3D contour CoMFA/CoMSIA maps provided an interpretable explanation of SAR for the compounds and also permitted interesting conclusions about the substituent effects at different positions of the biphenyl benzoic acid derivatives. CPH can also provide a powerful template for virtual screening and design of new b 3 -AR agonists.
Bioorganic & Medicinal Chemistry Letters, 1998
nM) and L-750,355 (29, 1~3 ECs0 = 13 nM) are selective partial agonists of the human receptor, with 33% and 49% activation, respectively. Both stimulate lipolysis in rhesus monkeys (EDs0 = 2 and 0.8 mg/kg, respectively), with minimal effects on heart rate. Oral bioavailability in dogs, 41% for L-749,372 and 47% for L-750,355, is improved relative to phenol analogs. .
Journal of Medicinal Chemistry, 2013
β-Adrenoceptor antagonists boast a 50-year use for symptomatic control in numerous cardiovascular diseases. One might expect highly selective antagonists are available for the human βadrenoceptor subtype involved in these diseases, yet few truly β 1 -selective molecules exist. To address this clinical need, we re-evaluated LK 204-545 (1), 1 a selective β 1 -adrenoceptor antagonist, and discovered it possessed significant partial agonism. Removal of 1's aromatic nitrile afforded 19, a ligand with similar β 1 -adrenoceptor selectivity and partial agonism (log K D of −7.75 and −5.15 as an antagonist of functional β 1 -and β 2 -mediated responses, respectively, and 34% of the maximal response of isoprenaline (β 1 )). In vitro β-adrenoceptor selectivity and partial agonism of 19 were mirrored in vivo. We designed analogues of 19 to improve affinity, selectivity, and partial agonism. Although partial agonism could not be fully attenuated, SAR suggests that an extended alkoxyalkoxy side chain, alongside substituents at the meta-or para-positions of the phenylurea, increases ligand affinity and β 1selectivity.
Tools to study β3-adrenoceptors
Naunyn-Schmiedeberg's Archives of Pharmacology, 2007
β 3 -adrenoceptors mediate some of the effects of catecholamines on tissues such as blood vessels or the urinary bladder and are putative targets for the treatment of diseases such as the overactive bladder syndrome. Progress in the understanding of the presence, function, and regulation of β 3 -adrenoceptors has been hampered by a lack of highly specific tools. "Classical" β 3 -adrenoceptor agonists such as BRL 37,344 [(R*, R*)-(±)-4[2-[(3-chlorophenyl)-2-hydroxyethyl) amino] propyl] phenoxyacetic acid] and CGP 12,177 [(±)-4-(3-t-butylamino-2-hydroxypropoxy)benzimidazol-2-one] are only partial agonists in many settings, have limited selectivity over other βadrenoceptor subtypes, and may additionally act on receptors other than β-adrenoceptors. More efficacious and more selective agonists have been reported and, in some cases, are in clinical development but are not widely available for experimental studies. The widely used antagonist SR 59,230 [3-(2-ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanoloxalate] is not selective for β 3 -adrenoceptors, at least in humans, and may actually be a partial agonist. Radioligands, which are suitable either for the selective labeling of β 3adrenoceptors or for the nonselective labeling of all βadrenoceptor subtypes, are also missing. β 3 -and β 1 /β 2 double knockout mice have been reported, but their usefulness for extrapolations in humans is questionable based upon major differences between humans and rodents with regard to the ligand recognition and expression profiles of β 3 -adrenoceptors. While the common availability of more selective agonists and antagonists at the β 3adrenoceptor is urgently awaited, the limitations of the currently available tools need to be considered in studies of β 3 -adrenoceptor for the time being.