Synthesis and Structure−Activity Relationships of N-Propyl-N-(4-pyridinyl)-1H-indol-1-amine (Besipirdine) and Related Analogs as Potential Therapeutic Agents for Alzheimer's Disease

Abstract

A series of novel N-(4-pyridinyl)-1H-indol-1-amines and other heteroaryl analogs was synthesized and evaluated in tests to determine potential utility for the treatment of Alzheimer's disease. From these compounds, N-propyl-N-(4-pyridinyl)-1H-indol-1-amine (besipirdine, 4c) was selected for clinical development based on in-depth biological evaluation. In addition to cholinomimetic properties based initially on in vitro inhibition of [3H]quinuclidinyl benzilate binding, in vivo reversal of scopolamine-induced behavioral deficits, and subsequently on other results, 4c also displayed enhancement of adrenergic mechanisms as evidenced in vitro by inhibition of [3H] clonidine binding and synaptosomal biogenic amine uptake, and in vivo by reversal of tetrabenazine-induced ptosis. The synthesis, structure-activity relationships for this series, and the biological profile of 4c are reported.

Anti‐Obsessional and Antidepressant Profile of Besipirdine

“…In behavioral studies, besipirdine significantly attenuated the amnesic effect of scopolamine on passive-avoidance retention. This test has been previously associated with a high probability of false positives (77,78), however, and results from our laboratories show that a2 antagonists can also reverse the effect of scopolamine in this test (52). Besipirdine reversed deficits in a 72-h passive-avoidance test involving either combined lesions of the nucleus basalis of Meynert (nbM) with ibotenic acid and either 6-hydroxydopamine (6-OHDA) administration to the ascending noradrenergic bundle or i.p.…”

“…In addition to the noradrenergic and serotonergic properties described above, besipirdine may possess cholinomimetic effects in vitro and in vivo (19,44,52) but the biochemical mechanism of action at a defined cholinergic target is unclear. For example, neither besipirdine nor P7480 inhibited rat brain acetylcholinesterase (44,52).…”

“…In addition to the noradrenergic and serotonergic properties described above, besipirdine may possess cholinomimetic effects in vitro and in vivo (19,44,52) but the biochemical mechanism of action at a defined cholinergic target is unclear. For example, neither besipirdine nor P7480 inhibited rat brain acetylcholinesterase (44,52). Although besipirdine displaced [3H]QNB, [3H]pirenzepine, [3H]N-methylscopolamine, and [3H]oxotremorine-M from rat brain muscarinic receptors in the sub-micromolar range, it failed to show activity as either an agonist or antagonist in classical muscarinic assays ( Table 4).…”

Applications of aminocarbazoles in heterocyclic synthesis

“…The amino carbazole derivative has the potential of being active against Alzheimer's disease since the presence of an amino group at the indole nucleus has shown promising results as a rehabilitative medicine. 31 1-Aminocarbazoles have been identified as Bcl-2 protein inhibitors, 32 NPY5 antagonists, 33 and anion receptors. 34 Aminocarbazoles are also useful intermediates for syntheses of various dyes and pigments, stabilizers for polymers, pesticides, photographic materials and diagnostic reagents in cytochemical studies.…”

Facile Synthesis of Substituted Furo- and Pyrano-Carbazoles

“…[15] Incorporation of amino groups into the carbazole systems would enhance the hydrophilicity of the molecule and therefore increase their water solubility. [16] Further, the sulfur atom will enhance Notes.…”