Improvement in the Selectivity and Metabolic Stability of the Serotonin 5-HT_1A Ligand, S 15535:  A Series of cis- and trans-2-(Arylcycloalkylamine) 1-Indanols

Abstract

S 15535 (1) displays a distinctive profile of agonist and antagonist (weak partial agonist) activity at pre- and postsynaptic 5-HT(1A) receptors, respectively. It has proven to be active in several models predictive of anxiolytic, antidepressant, and procognitive properties. In an attempt to increase its selectivity and metabolic stability, and guided by the results of human metabolic studies, we prepared a series of cis- and trans-2-(arylcycloalkylamine) 1-indanols. Irrespective of the nature of the arylcycloalkylamine moiety or the presence of substituents on the indanol ring, trans isomers invariably showed the highest affinity for human, recombinant h5-HT(1A) receptors. Among them, compounds 39, 42, 45, 49, 52, 53, 54, 57, 61, 64, 67, and 70 displayed similar or higher affinity than the parent compound 1 (pK(i) > or = 9.1). Lack of selectivity toward alpha1-adrenoceptors has been frequently encountered with 5-HT(1A) ligands. While S 15535 itself presents reasonable selectivity (158-fold) in this respect, trans piperazine derivatives 4-trans,35, 39, 41, 47, 64, 68, 69, 70, 71 displayed even more pronounced selectivity vs alpha1-adrenoceptors, with the nitro derivative 70 being highly selective (1259-fold). However, among the set of trans piperidines prepared, only 64, which also bears a nitro on the indanol ring, displayed selectivity greater than the parent compound 1. All trans derivatives behaved as partial agonists at h5-HT(1A) receptors, as determined by their submaximal stimulation of [35S]GTPgammaS binding to a level comparable to that observed with S 15535. In metabolic stability studies in vitro using human microsomes and hepatocytes, only trans piperazines and, in particular, 35, 39, 41, 68, 69, and 70, showed an improvement relative to 1, whereas trans piperidines did not. Compounds 35, 39, 41, and 70, which combined both improved selectivity and metabolic stability, and which retained the distinctive pharmacological characteristics of S 15535, were evaluated in animal models of anxiety. Of these, 35, which showed the highest oral bioavailability in vivo in rats, was resolved into its two isomers 36 and 37. The eutomer 37 displayed 47% oral bioavailability in the rat and was potently active (0.1-0.5 mg/kg, s.c.) in the rat ultrasonic vocalization and social interaction models, predictive of anxiolytic activity. In conclusion, 2-(arylcycloalkylamine) 1-indanols represent a novel class of potent 5-HT(1A) ligands in which the presence of the hydroxyl group in the benzylic position enhances selectivity, while substituents on the phenyl ring of the indanol moiety improve both selectivity and metabolic stability.

Identification of a new series of benzothiazinone derivatives with excellent antitubercular activity and improved pharmacokinetic profiles

“…4-Nitrobenzenesulfonyl chloride was dropped into a suspension of the triuoroacetate and trimethylamine at 0 C bath in dichloromethane to give the desired acetamide 13-16, then the piperazinones (17-20) were formed by further reaction with 1,2-dibromoethane. Treatment of 17-20 with methylmercaptopropionate in acetonitrile/DMSO (v/v 49/1) at 50 C gave the desired compounds (21)(22)(23)(24) in 69.06% overall yield starting from 1-4. Analogue 41-48 was synthesized from the corresponding benzoyl chloride (25-32) in 73.02% yield over two steps as shown in Scheme 2 via nucleophilic substitution of compounds 25-32 with 1-Boc-4-hydroxypiperidine followed by deprotection the Boc-group.…”

Murine Efficacy and Pharmacokinetic Evaluation of the Flaviviral NS5 Capping Enzyme 2-Thioxothiazolidin-4-One Inhibitor BG-323

“…Other successful strategies for increasing metabolic stability rely on the specificity of metabolic enzymes for their substrates. Changing chirality [32], reducing lipophilicity [33] and changing the size of cyclized groups within the molecule [30] have also been shown to have a favorable effect on small molecule stability. The application of one or more of these strategies to BG-323 could stabilize the compound sufficiently to increase the half-life and potentially increase the ability of the BG-323 to inhibit viral replication in vivo .…”

Design and Synthesis of Conformationally Constrained RORγt Inverse Agonists

“…The N-linked diazepane 34 and 1,3-substituted piperidine 36 that were expected to form a Ushaped conformation [14] showed potent activity. [15] Therefore, further modification on the central parts of 5 and 36 was carried out. Among the cyclized scaffolds, 1,2-substututed cis-cyclopentyl 5 and 1,3substituted piperidine 36 showed more potent reporter activity.…”