Bjarne Brudeli

Synthesis and pharmacological properties of novel hydrophilic 5-HT4 receptor antagonists

Serotonin (5-hydroxytryptamine, 5-HT) is an important signalling molecule in the human body. The 5-HT(4) serotonin receptor, coupled to the G protein G(s), plays important physiological and pathophysiological roles in the heart, urinary bladder, gastrointestinal tract and the adrenal gland. Both 5-HT(4) antagonists and agonists have been developed in the aim to treat diseases in these organs. 5-HT(4) agonists might have beneficial effects in the central nervous system (CNS) and therefore, 5-HT(4) antagonists might cause CNS side effects. In this study, we have developed new amphoteric 5-HT(4) antagonists. A series of cyclic indole amide derivatives possessing an oxazine ring and a piperidine alkane carboxylic acid side chain and the corresponding prodrug esters were synthesized and their binding to 5-HT(4) receptors and antagonist properties were evaluated. In addition, an indole ester without the oxazine ring and the corresponding indole amide derivatives were also tested. Octanol-water distribution (LogD(Oct7.4)) was tested for some of the synthesized ligands. The main structure-affinity characteristics of the 5-HT(4) compounds tested were that the prodrug esters show higher affinity than their corresponding free acids, indole esters show higher affinity than the corresponding amides and ligands containing the oxazine ring in the indole skeleton show higher affinity than indole derivatives not containing the ring. One representative prodrug ester and its corresponding free acid were tested for binding on a panel of receptors and showed preserved selectivity for the 5-HT(4) receptor. These new molecules may be useful to target peripheral 5-HT(4) receptors.

Acidic biphenyl derivatives: synthesis and biological activity of a new series of potent 5-HT(4) receptor antagonists.

Serotonin (5-hydroxytryptamine, 5-HT) is an important signaling molecule in the central nervous system (CNS) and in non-neuronal tissues and organs. Serotonin mediates a positive chronotropic and inotropic response through 5-HT4 receptors in the atrium and ventricle of the heart. Recent investigations have revealed increased expression of the 5-HT4(b) isoform in cardiomyocytes of chronic arrhythmic and failing hearts, and that the use of 5-HT4 receptor antagonists may be beneficial for treating these conditions. The 5-HT4 receptor possesses a transmembrane (TM) binding site important for ligand affinity and recognition, as well as a capacity to accommodate bulky ligands. A new series of peripherally-acting 5-HT4 receptor antagonists were prepared by combining the acidic biphenyl group from the class of angiotensin II receptor blockers (ARBs) with the SB207266 (piboserod) scaffold. The new compounds were pharmacologically evaluated and carboxylic acid 21 was identified as a potent and promising 5-HT4 receptor antagonist with moderate affinity for the AT1 receptor. The permeability of carboxylic acid 21 in a Caco-2 assay was low and the corresponding prodrug esters 23a-f were therefore prepared. The pharmacokinetics of methyl ester 20 and n-butyl ester 23c were evaluated in a rat model, revealing incomplete metabolism to carboxylic acid 21. However, methyl ester 20 is a potent 5-HT4 receptor antagonist with binding affinities in the low picomolar range. Methyl ester 20 has promising oral bioavailability and pharmacokinetics and may target 5-HT4 receptors in both CNS and peripheral organs.

Synthesis and pharmacological properties of a new hydrophilic and orally bioavailable 5-HT4 antagonist.

5-HT4 receptor antagonists have been suggested to have clinical potential in treatment of atrial fibrillation, diarrhea-prone irritable bowel syndrome and urinary incontinence. Recently, the use of 5-HT4 antagonists has been suggested to have a therapeutic benefit in heart failure. Affinity for the hERG potassium ion channel and increased risk for prolonged QT intervals and arrhythmias has been observed for several 5-HT4 ligands. Serotonin may also have beneficial effects in the central nervous system (CNS) through stimulation of the 5-HT4 receptor, and reduced distribution of 5-HT4 antagonists to the CNS may therefore be an advantage. Replacing the amide and N-butyl side chain of the 5-HT4 receptor antagonist SB207266 with an ester and a benzyl dimethyl acetic acid group led to compound 9; a hydrophilic 5-HT4 antagonist with excellent receptor binding and low affinity for the hERG potassium ion channel. To increase oral bioavailability of carboxylic acid 9, two different prodrug approaches were applied. The tert-butyl prodrug 11 did not improve bioavailability, and LC-MS analysis revealed unmetabolized prodrug in the systemic circulation. The medoxomil ester prodrug 10 showed complete conversion and sufficient bioavailability of 9 to advance into further preclinical testing for treatment of heart failure.

Discovery and pharmacological profile of new hydrophilic 5-HT(4) receptor antagonists.

The synthesis and pharmacological data of some new and potent hydrophilic 5-HT4 receptor antagonists are described. Propanediol derivative 25 was identified as a potent antagonist with low affinity for the hERG potassium channel and promising pharmacokinetics.