2-Aryl Indole NK1 receptor antagonists: optimisation of indole substitution

Cooper, Laura C.; Chicchi, Gary G.; Dinnell, Kevin; Elliott, Jason; Hollingworth, Gregory J.; Kurtz, Marc M.; Locker, Karen L; Morrison, Denise; Shaw, Duncan; Tsao, Kwei-Lan; Watt, Alan P.; Williams, Angela; Swain, Christopher J.

doi:10.1016/s0960-894x(01)00182-2

Cited by 70 publications

(18 citation statements)

References 14 publications

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“…The bromoderivative shown below (Fig. (21)) was reported to have the highest affinity in an in vitro NK 1 binding assay from a combinatorial library (hNK 1 IC 50 = 1.0 nM) and was also shown to be a substance P antagonist [62]. Disappointingly, the compound exhibited poor in vivo activity as well as poor pharmacokinetics, having a bioavailability of only 3% in the rat.…”

Section: Neurokinin-1 (Nk 1 ) Receptor Antagonistsmentioning

confidence: 99%

“…Nevertheless, its promising in vitro activity and structural novelty was a good starting point for further research. Replacement of the bromine with chlorine seems to improve the binding affinity, with an IC 50 of 0.6 nM [62].…”

Section: Neurokinin-1 (Nk 1 ) Receptor Antagonistsmentioning

confidence: 99%

“…(22) (left). [62][63][64]. Combining these changes with other optimal groups gave rise to the compound depicted in Fig.…”

Section: Neurokinin-1 (Nk 1 ) Receptor Antagonistsmentioning

confidence: 99%

“…(22), which also displayed impressive NK 1 receptor binding affinity with an IC 50 of 0.16 nM and an ID 50 of 0.3 mg/kg (i.v. route) when tested in the gerbil foot-tapping assay [62][63][64]. It was tentatively proposed that methylation of the indole ring nitrogen served to increase the steric bulk around nitrogen and produced a favourable conformation for receptor binding [63].…”

Section: Neurokinin-1 (Nk 1 ) Receptor Antagonistsmentioning

confidence: 99%

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2-Arylindoles: A Privileged Molecular Scaffold with Potent, Broad-Ranging Pharmacological Activity

Snape²

2012

CMC

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Privileged structures bind to multiple receptors with high affinity, thus aiding the development of novel biologically active compounds. Indoles are classed as privileged structures, and as a result of the indole nucleus being present in a broad range of biologically active molecules, it has been suggested that indoles probably represent the most important of all structural classes in drug discovery. Amongst the indole class of compounds is a particular subset - 2-arylindoles - which appear to be a most promising lead for drug development. This review summarises the wide-ranging activities of 2-arylindoles and some of their important biological activities reported in the literature over the past two decades.

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Section: Neurokinin-1 (Nk 1 ) Receptor Antagonistsmentioning

confidence: 99%

Section: Neurokinin-1 (Nk 1 ) Receptor Antagonistsmentioning

confidence: 99%

“…(22) (left). [62][63][64]. Combining these changes with other optimal groups gave rise to the compound depicted in Fig.…”

Section: Neurokinin-1 (Nk 1 ) Receptor Antagonistsmentioning

confidence: 99%

Section: Neurokinin-1 (Nk 1 ) Receptor Antagonistsmentioning

confidence: 99%

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2-Arylindoles: A Privileged Molecular Scaffold with Potent, Broad-Ranging Pharmacological Activity

Snape²

2012

CMC

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“…5-Trifluoromethoxyindole 16 bearing a pendant amide substituent at the 3-position was obtained through a polymer supported synthetic procedure shown in Scheme 5 (21). These compounds were investigated as NKj antagonists.…”

Section: Indolesmentioning

confidence: 99%