Development of high-affinity 5-HT3 receptor antagonists. 1. Initial structure-activity relationship of novel benzamides

Abstract

This report describes the development of novel benzamides which are orally active, highly potent, specific antagonists of 5-HT3 receptors. Described in this first report are the structure-activity relationships that led to novel structures with improved potency and selectivity. From this series of compounds, (S)-28 was identified and selected for further evaluation as a 5-HT3 receptor antagonist. Compared with 5-HT3 antagonists such as GR 38032F, BRL 43694, and metoclopramide, (S)-28 was most active in (a) inhibiting binding to 5-HT3 receptor binding sites in rat entorhinal cortex with an Ki value of 0.19 nM and (b) blocking cisplatin-induced emesis in the ferret with an ED50 value determined to be 9 micrograms/kg po.

Probing the Existence of a Metastable Binding Site at the β2-Adrenergic Receptor with Homobivalent Bitopic Ligands

“…TLC R f = 0.30 (20% EtOAc in n -heptane, v/v); 1 H NMR (400 MHz, CDCl 3 ): δ 7.23–7.16 (m, 1H), 7.15–7.11 (m, 1H), 7.11–7.05 (m, 1H), 6.99 (dd, J = 1.0, 8.0 Hz, 1H), 2.74 (t, J = 7.5 Hz, 2H), 2.38 (t, J = 7.0 Hz, 2H), 2.10 (pen, J = 7.0 Hz, 2H); 13 C NMR (101 MHz, CDCl 3 ): δ 171.4, 151.8, 130.0, 129.7, 128.3, 125.9, 119.2, 31.0, 28.2, 26.5. The data are agreement with that reported by others …”

Phenylimidazolidin-2-one Derivatives as Selective 5-HT3 Receptor Antagonists and Refinement of the Pharmacophore Model for 5-HT3 Receptor Binding

“…Compounds with only one hydrophobic substituent on the phenyl ring in a meta position from the imidazole and quinuclidine series have a greater potency than the corresponding unsubstituted structures (compare 21 and 29 ; 56 and 59 ). The same pattern of activity has been reported for 5-HT 3 receptor antagonists, belonging to other chemical series. , However, among the compounds we prepared, the meta-substituted molecules have a potency lower than that of the corresponding double-meta-substituted ones ( 28, 58 , and 63 ) . In our model, the chloro atom of the para-substituted inactive compounds 25 and 64 occupies the space located between the two hydrophobic sites (Figure ).…”

“…The same pattern of activity has been reported for 5-HT 3 receptor antagonists, belonging to other chemical series. 30,31 However, among compounds we prepared, the meta-substituted molecules have a potency lower than that of the corre- a None of the compounds showed affinity for D1, D2, R1, R2, M1+2, 5-HT1, 5-HT1A, 5-HT2, and 5-HT4 receptor binding sites (IC50 >10 µM), or agonistic (EC50 >1 µM) or antagonistic activity (Kb > 1 µM) on rat oesophagus preparation (5-HT4 receptor). sponding double-meta-substituted ones (28, 58, and 63).…”

Inhibition of E-Selectin-, ICAM-1-, and VCAM-1-Mediated Cell Adhesion by Benzo[b]thiophene-, Benzofuran-, Indole-, and Naphthalene-2-carboxamides: Identification of PD 144795 as an Antiinflammatory Agent

“…Catalytic reduction of the 5-nitro derivative 7 provided the 5-amino analog 9. The 5-hydroxy derivative 10 was obtained by deprotection of the 5-benzyloxy analog 8. The secondary amides [17][18][19][20][21] resulted from the reaction of the imidazolide of 3 with primary amines (Scheme 1).…”