Christophe Rochais

Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment.

Significance Targeting more than one molecular cause implied in the pathogenesis of Alzheimer’s disease (AD) with a sole drug is considered a promising challenge, because it may address the numerous failures that recently occurred during clinical trials that were conducted in this area. Donecopride has been designed by us as a multitarget-directed ligand, targeting both serotonin subtype 4 receptor and acetylcholinesterase with excellent in vitro activities. The latter seems able to not only restore the cholinergic neurotransmission altered in AD but also, promote the secretion of a neurotrophic protein that is detrimental to the neurotoxic amyloid-β peptide. With its excellent drugability, donecopride further displayed significant procognitive effects in mice and generated a promising lead for a previously unidentified approach in AD treatment. RS67333 is a partial serotonin subtype 4 receptor (5-HT4R) agonist that has been widely studied for its procognitive effect. More recently, it has been shown that its ability to promote the nonamyloidogenic cleavage of the precursor of the neurotoxic amyloid-β peptide leads to the secretion of the neurotrophic protein sAPPα. This effect has generated great interest in RS67333 as a potential treatment for Alzheimer’s disease (AD). We show herein that RS67333 is also a submicromolar acetylcholinesterase (AChE) inhibitor and therefore, could contribute, through this effect, to the restoration of the cholinergic neurotransmission that becomes altered in AD. We planned to pharmacomodulate RS67333 to enhance its AChE inhibitory activity to take advantage of this pleiotropic pharmacological profile in the design of a novel multitarget-directed ligand that is able to exert not only a symptomatic but also, a disease-modifying effect against AD. These efforts allowed us to select donecopride as a valuable dual (h)5-HT4R partial agonist (Ki = 10.4 nM; 48.3% of control agonist response)/(h)AChEI (IC50 = 16 nM) that further promotes sAPPα release (EC50 = 11.3 nM). Donecopride, as a druggable lead, was assessed for its in vivo procognitive effects (0.1, 0.3, 1, and 3 mg/kg) with an improvement of memory performances observed at 0.3 and 1 mg/kg on the object recognition test. On the basis of these in vitro and in vivo activities, donecopride seems to be a promising drug candidate for AD treatment.

Synergistic effect of acetylcholinesterase inhibition (donepezil) and 5-HT(4) receptor activation (RS67333) on object recognition in mice.

Facing inefficiency of current treatments to cure Alzheimer disease (AD), a pharmacological approach is now emerging on the assumption that a single compound may be able to hit multiple targets, namely Multi-Target-Directed Ligands (MTDLs). Displaying numerous advantages, several MTDL for AD have been recently described but none associating an inhibition of AChE and an activation of 5-HT(4)R. The aim of this study was to validate the concept of a synergistic action of these two targets on episodic-like memory performances in mice. Among potent molecules, RS67333, a reference 5-HT(4)R agonist and donepezil (DNPZ), a reference acetylcholinesterase inhibitor, have been particularly chosen because of their close chemical structure. Administered separately, RS67333 (0.3 and 1mg/kg) and DNPZ (1mg/kg) improved recognition performances compared to saline treated animals but not with lower doses. Co-administration of subactive doses of RS67333 (0.1mg/kg) and DNPZ (0.3mg/kg) improved memory, moreover, this improvement is prevented if a 5-HT(4)R antagonist (GR125487, 10mg/kg) is also administered. Activation of 5-HT(4)R combined with inhibition of AChE with subactive doses of RS67333 and of DNPZ has synergistic effects on memory performances in mice. These molecules having close chemical structures, the synergistic effect of their combination affords new hope to chemist for the synthesis of MTDL.

Synthesis of new dipyrrolo- and furopyrrolopyrazinones related to tripentones and their biological evaluation as potential kinases (CDKs1-5, GSK-3) inhibitors.

We herein describe the synthesis of novel dipyrrolo- and furopyrrolopyrazinones related to highly cytotoxic tripentones and to their oximes. The synthetic pathway involved in particular a Curtius rearrangement and a subsequent cyclisation into the title pyrazinones. The biological evaluation towards various cyclin-dependent kinases (CDKs1-5, GSK-3) highlighted a weak inhibitory activity for the oximes whose SAR was studied by a molecular modeling study.

Therapeutic Potential of 5-HT6 Receptor Agonists

Given its predominant expression in the central nervous system (CNS), 5-hydroxytryptamine (5-HT: serotonin) subtype 6 receptor (5-HT6R) has been considered as a valuable target for the development of CNS drugs with limited side effects. After 2 decades of intense research, numerous selective ligands have been developed to target this receptor; this holds potential interest for the treatment of neuropathological disorders. In fact, some agents (mainly antagonists) are currently undergoing clinical trial. More recently, a series of potent and selective agonists have been developed, and preclinical studies have been conducted that suggest the therapeutic interest of 5-HT6R agonists. This review details the medicinal chemistry of these agonists, highlights their activities, and discusses their potential for treating cognitive issues associated with Alzheimers disease (AD), depression, or obesity. Surprisingly, some studies have shown that both 5-HT6R agonists and antagonists exert similar procognitive activities. This article summarizes the hypotheses that could explain this paradox.

Tripentones: A Promising Series of Potent Anti-Cancer Agents

The 8H-thieno[2,3-b]pyrrolizinones, some of which exert very potent cytotoxic activity against tumor cell lines in vitro, are a promising novel series of anti-cancer agents. These compounds belong to the tripentone family and are based on 9H-pyrrolo[1,2-a]indol-9-one derivatives and their heterocyclic isosteres. This paper inventories the different synthetic strategies for tripentones and reviews their biological effects and therapeutic potential.

Chronic activation of 5-HT4 receptors or blockade of 5-HT6 receptors improve memory performances.

5-HT4 and 5-HT6 serotonergic receptors are located in brain structures involved in memory processes. Neurochemical and behavioural studies have demonstrated that acute activation of 5-HT4 receptors (5-HT4R) or blockade of 5-HT6 receptors (5-HT6R) improves memory. To evaluate the potential of these two receptors as targets in the treatment of memory disorders encountered in several situations (ageing, Alzheimers disease, schizophrenia, etc.), it is necessary to assess whether their beneficial effects occur after chronic administration, and if such treatment induces adverse effects. The goal of this study was to assess the effects of chronic 5-HT4R or 5-HT6R modulation on recognition memory, and to observe the possible manifestation of side effects (modification of weight gain, locomotor activity or exploratory behaviour, etc.). Mice were treated for 14 days with a 5-HT4R partial agonist (RS-67333) or a 5-HT6R antagonist (SB-271046) at increasing doses. Memory performances, locomotor activity, and exploration were assessed. Both chronic 5-HT4R activation and 5-HT6R blockade extended memory traces in an object recognition test, and were not associated with any adverse effects in the parameters assessed. Chronic modulation of one or both of these receptors thus seems promising as a potential strategy for the treatment memory deficits.

Hydrogenative desulphurization of thienopyrrolizinones: an easy and selective access to (Z)-phenethylidenepyrrolizinones with in vitro cytotoxic activity.

Attempts in view to dearomatize some previously reported tripentones with potent antineoplastic activities led in thiophene series to an unexpected hydrogenative desulphurization reaction. The resulting (Z)-phenethylidenepyrrolizinones were tested in vitro over human epidermoid carcinoma KB cell line. The results of this biological evaluation indicated that the tricyclic core of our model can be cleaved with a partial respect of the activity.

3-(Dipropylamino)-5-hydroxybenzofuro[2,3-f]quinazolin-1(2H)-one (DPA-HBFQ-1) plays an inhibitory role on breast cancer cell growth and progression.

A series of unknown 3-(alkyl(dialkyl)amino)benzofuro[2,3-f]quinazolin-1(2H)-ones 4-17 has been synthesized as new ellipticine analogs, in which the carbazole moiety and the pyridine ring were replaced by a dibenzofuran residue and a pyrimidine ring, respectively. The synthesis of these benzofuroquinazolinones 4-17 was performed in a simple one-pot reaction using 3-aminodibenzofuran or its 2-methoxy derivative, as starting materials. From 3-(dipropylamino)-5-methoxybenzofuro[2,3-f] quinazolin-1(2H)-one (13), we prepared 3-(dipropylamino)-5-hydroxybenzofuro[2,3-f]quinazolin-1(2H)-one (18), referred to as DPA-HBFQ-1. The cytotoxic activities of all the synthesized compounds, tested in different human breast cancer cell lines, revealed that DPA-HBFQ-1 was the most active compound. In particular, the latter was able to inhibit anchorage-dependent and -independent cell growth and to induce apoptosis in estrogen receptor alpha (ERα)-positive and -negative breast cancer cells. It did not affect proliferation and apoptotic responses in MCF-10A normal breast epithelial cells. The observed effects have been ascribed to an enhanced p21(Cip1/WAF1) expression in a p53-dependent manner of tumor suppressor and to a selective inhibition of human topoisomerase II. In addition, DPA-HBFQ-1 exerted growth inhibitory effects also in other cancer cell lines, even though with a lower cytotoxic activity. Our results indicate DPA-HBFQ-1 as a good candidate to be useful as cancer therapeutic agent, particularly for breast cancer.

Indenopyrazole oxime ethers: synthesis and β1-adrenergic blocking activity.

This paper reports the synthesis and cardiac activity of new β-blockers derived from (Z/E)-indeno[1,2-c]pyrazol-4(1H)-one oximes (5a,b). The latter compounds were allowed to react with epichlorohydrin, followed by reacting the oxiranyl derivatives formed (6a,b) with some aliphatic amines to give the target compounds (Z/E)-1-phenyl-1H-indeno[1,2-c]pyrazol-4-one O-((2-hydroxy-3-(substituted amino)propyl)oxime (7a-c) and (Z/E)-1-methyl-1H-indeno[1,2-c]pyrazol-4-one O-((2-hydroxy-3-(substituted amino)propyl)oxime (8a-c). These final products 7a-c and 8a-c were evaluated for their ability to modulate the cardiac performance of a prototype mammalian heart. The results showed that, out of these molecules tested, 7b elicits a more potent depressant effect on contractility and relaxation, and competitively antagonizes β1-adrenergic receptors.

Synthesis of novel 7-oxo and 7-hydroxy trifluoroallocolchicinoids with cytotoxic effect.

The synthesis of 7-oxo and 7-hydroxy trifluoroallocolchicinoids was achieved through the intramolecular cyclization of o-phenyl-β-phenylalanines. The resulting compounds were evaluated for their cytotoxic activity against KB cells and their inhibitory effect towards the polymerization of tubulin. The results yielded some potent cytotoxic compounds with correlated partial antitubulin effect.