2002
DOI: 10.1016/s0960-894x(02)00250-0
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4,4-Disubstituted cyclohexylamine NK1 receptor antagonists II

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Cited by 16 publications
(5 citation statements)
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“…d). Cooper et al . also established that substituting the peripheral fluorine‐attached ring with a spiroether in the structure of neurokinin 1 inhibitor can diminish its hERG affinity by atleast 50% (Fig.…”
Section: Small Molecule Optimization For Herg Activitymentioning
confidence: 99%
See 1 more Smart Citation
“…d). Cooper et al . also established that substituting the peripheral fluorine‐attached ring with a spiroether in the structure of neurokinin 1 inhibitor can diminish its hERG affinity by atleast 50% (Fig.…”
Section: Small Molecule Optimization For Herg Activitymentioning
confidence: 99%
“…Table lists some of the drugs (along with their molecular structures), those discontinued by the FDA due to prolongation of QT interval. Many such drugs with hERG liability are being increasingly documented in the literature and other databases, such as crediblemeds and Pubchem bioassay. Thus, drug‐induced hERG blockade has become one of the prime safety issues in drug regulation and development.…”
Section: Introductionmentioning
confidence: 99%
“…In a 2002 report, Cooper et al 62 made significant changes to the peripheral aryl rings in order to achieve separation between NK1 activity and IKr. Replacement of the terminal fluorophenyl ring of 52 with the spiroether system in 53 led to a reduction in IKr activity of around 50-fold, with conservation of activity at the primary target.…”
Section: Control Of Log Pmentioning
confidence: 99%
“…These include subtle peripheral structural modifications, removing distal aryl groups, adding an acidic function or its bioisostere, decreasing lipophilicity, decreasing pK a of the most basic nitrogen, introducing geometric constraints, and changing molecular shape. [3][4][5]7,9,[25][26][27][28][29][30][31][32][33][34][35] Although it has been shown that all of these approaches work in particular cases, none of them is a panacea. The main drawback of these approaches is that, as well as decreasing potency at the hERG channel, they more than often simultaneously decrease the potency at the intended target.…”
Section: Introductionmentioning
confidence: 99%
“…A number of hERG channel pharmacophores have been developed, with the key determinants being a protonated basic nitrogen surrounded by several aromatic or hydrophobic groups. ,, , It has been found that a hydrogen-bond (H-bond) acceptor or an electron-withdrawing atom located at the periphery of the molecule may also contribute to high-affinity binding to hERG. ,,,,, Based on these studies, a number of lead optimization approaches to avoid hERG blockage have been proposed. These include subtle peripheral structural modifications, removing distal aryl groups, adding an acidic function or its bioisostere, decreasing lipophilicity, decreasing p K a of the most basic nitrogen, introducing geometric constraints, and changing molecular shape. ,,, Although it has been shown that all of these approaches work in particular cases, none of them is a panacea. The main drawback of these approaches is that, as well as decreasing potency at the hERG channel, they more than often simultaneously decrease the potency at the intended target. …”
Section: Introductionmentioning
confidence: 99%