3-(4-Fluoropiperidin-3-yl)-2-phenylindoles as High Affinity, Selective, and Orally Bioavailable h5-HT_2A Receptor Antagonists

Abstract

The development of very high affinity, selective, and bioavailable h5-HT(2A) receptor antagonists is described. By investigation of the optimal position for the basic nitrogen in a series of 2-phenyl-3-piperidylindoles, it was found that with the basic nitrogen at the 3-position of the piperidine it was not necessary to further substitute the piperidine in order to obtain good binding at h5-HT(2A) receptors. This meant the compounds no longer had high affinity at the IKr potassium channel, an issue with previous series of 2-aryl-3-(4-piperidyl)indoles. Improvements could be made to oral bioavailability in this series by reduction of the pK(a) of the basic nitrogen, by adding a fluorine atom to the piperidine ring, leading to 3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (17). Metabolic studies with this compound identified oxidation at the 6-position of the indole as a major route in vitro and in vivo in rats. Blocking this position with a fluorine atom led to 6-fluoro-3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (22), an antagonist with 0.06 nM affinity for h5-HT(2A) receptors, with bioavailability of 80% and half-life of 12 h in rats.

Novel Bayesian classification models for predicting compounds blocking hERG potassium channels

“…It has been reported that D 3 receptor antagonists tend to exhibit hERG toxicity [53] . The top 11-20 of the good features are from sertindole analogues, Wombat-PK database molecules and h5-HT 2A receptor antagonists, which are mostly strong hERG blockers [48,54,55] . The good features can be used as structural alerts for hERG toxicity.…”

Fluorine in Peptide Design and Protein Engineering

“…Another impact of fluorine on the bioavailability of a bioactive compound is the enhancement of its pharmacokinetic properties and of membrane binding and permeation. This effect can be achieved either by weakening the basicity of a functional group, for example a nitrogen atom, [40] due to the electron-withdrawing capability of fluorine, [37] or by a general increase in the lipophilicity of the molecule. [41] The ability to diffuse across membranes is indispensable for drugs that are supposed to have cerebral pharmacological effects, since they must pass through the blood-brain barrier.…”

Fluorination methods in drug discovery

“…86 For instance, the 3-piperidinylindole derivative 129 ( Figure 18) binds to the human 5-HT 2A serotonin receptor, and was targeted as a promising antipsychotic drug lead. 87 However, the bioavailability of 129 was limited due to the basicity of the secondary amine group (positively charged at physiological pH). This inconvenience has been overcome by introducing a fluorine atom onto the piperidine ring (130, Figure 18), reducing the basicity of the secondary amine by nearly two orders of magnitude, resulting in a marked betterment The beneficial properties of benzyl fluorides in lead optimization 102,103 have motivated an intense research activity in late stage fluorination of benzylic positions.…”