Discovery and Pharmacological Profile of New 1H-Indazole-3-carboxamide and 2H-Pyrrolo[3,4-c]quinoline Derivatives as Selective Serotonin 4 Receptor Ligands

Abstract

Since the discovery of the serotonin 4 receptor (5-HT(4)R), a large number of receptor ligands have been studied. The safety concerns and the lack of market success of these ligands have mainly been attributed to their lack of selectivity. In this study we describe the discovery of N-[(4-piperidinyl)methyl]-1H-indazole-3-carboxamide and 4-[(4-piperidinyl)methoxy]-2H-pyrrolo[3,4-c]quinoline derivatives as new 5-HT(4)R ligands endowed with high selectivity over the serotonin 2A receptor and human ether-a-go-go-related gene potassium ion channel. Within these series, two molecules (11 ab and 12 g) were identified as potent and selective 5-HT(4)R antagonists with good in vitro pharmacokinetic properties. These compounds were evaluated for their antinociceptive action in two analgesia animal models. 12 g showed a significant antinociceptive effect in both models and is proposed as an interesting lead compound as a 5-HT(4)R antagonist with analgesic action.

Iodoindazoles with Selective Magnesiation at Position 3: A Route to Highly Functionalized Indazoles

“…[4] Indazole is found in manys ynthetic derivatives, particularly in the field of medicinal chemistry,i nw hich it is generally used as an isostere of indole. [5] Therefore, this scaffold was successfully used in drug development programs to afford anti-HIV [6] or anti-tumor agents, [7,8,9] cannabinoid, [10] 5-HT 2 , [11] 5-HT 3 [12] or 5-HT 4 [13,14] receptors ligands,k inase [15][16][17][18] or NO-synthase inhibitors. [19,20] Several indazole derivatives are now available as marketed drugs: granisetron,b endazac, benzydamine, or axitinib.…”

Targeting Serotonin 2A and Adrenergic α1Receptors for Ocular Antihypertensive Agents: Discovery of 3,4‐Dihydropyrazino[1,2‐b]indazol‐1(2H)‐one Derivatives

“…[17] The real startingp oint of the project was as et of binding resultso btained during ah it-to-lead program aimed at discovering selective 5-HT 4 receptor antagonists, and in particular,data obtained for the two indazole-amide isomers (4 and 5)s hown in Ta ble 1. [18] In the competition binding assay, the shift of the methyl group from the N1 (4)t ot he N2 position (5)o ft he indazole ring resulted in a3 00-fold decrease in 5-HT 4 receptor affinity,b ut affinity for the 5-HT 2A receptor was maintained. This sharp change in the receptor affinity profile, due to as ubtle structuralm odification,m ade possible ap romising scenario that prompted us to select the N2-substituted indazole-3-carboxamide scaffold as the starting point for our program.…”

An Efficient Five‐Component Reaction for the Synthesis of 4,4′‐((2‐Oxoindoline‐3,3‐diyl)bis(methylene))bis(2‐aryl‐1H‐pyrrolo[3,4‐c]quinoline‐1,3(2H)‐dione) Derivatives

“…Pyrrolo[3,4‐ c ]quinoline derivatives are a very important class of N ‐heterocycles with promising physiological activities, which often used as cytotoxic agents , ADAMTS‐4/5 inhibition , and 5‐HT3/4R inhibition or inverse agonists for GABA A (γ‐aminobutyric acid A) brain receptors . There are also the caspase‐3 inhibitors and serotonin 4 receptor ligands . Therefore, the efficient synthesis of pyrrolo[3,4‐ c ]quinoline derivatives has become important challenges for both synthetic and pharmaceutical chemists.…”