Giancarlo Merlo

5-Aryl-4-carboxamide-1,3-oxazoles: Potent and selective GSK-3 inhibitors

5-Aryl-4-carboxamide-1,3-oxazoles are a novel, potent and selective series of GSK-3 inhibitors. The optimization of the series to yield compounds with cell activity and brain permeability is described.

Phenylethynyl-pyrrolo[1,2-a]pyrazine: a new potent and selective tool in the mGluR5 antagonists arena.

The synthesis and the structure activity of a new series of pyrrolo[1,2-a]pyrazine is reported. These molecules are potent and selective non-competitive mGluR5 antagonists and may shed new light on the pattern of substitution tolerated by this receptor.

6-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones: dual-acting 5-HT1 receptor antagonists and serotonin reuptake inhibitors.

Investigation of a series 6-[2-(4-aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones has led to the discovery of potent 5-HT(1A/1B/1D) receptor antagonists with and without additional SerT affinity. Modulation of the different target activities gave compounds with a range of profiles suitable for further in vivo characterization.

Identification of 2-(4-pyridyl)thienopyridinones as GSK-3β inhibitors.

The discovery of a novel series of 2-(4-pyridyl)thienopyridinone GSK-3β inhibitors is reported. X-ray crystallography reveals its binding mode and enables rationalization of the SAR. The initial optimization of the template for improved cellular activity and predicted CNS penetration is also presented.

Novel 5-HT1A/1B/1D receptors antagonists with potent 5-HT reuptake inhibitory activity

Novel 2-methyl-5-quinolinyl-1-piperazinylalkyl-3,4-dihydro-2H-1,4-benzoxazin-3-ones showing high affinities for the 5-HT(1A/1B/1D) receptors coupled with potent 5-HT reuptake inhibitory activity have been discovered. This is the first report describing docking of the lead compound 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2H-1,4-benzoxazin-3(4H)-one 1, into a model of the 5-HT transporter and the 5-HT(1A) receptor model.

Discovery of 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (GSK163090), a Potent, selective, and orally active 5-HT1A/B/D receptor antagonist.

In an effort to identify selective drug like pan-antagonists of the 5-HT1 autoreceptors, studies were conducted to elaborate a previously reported dual acting 5-HT1 antagonist/SSRI structure. A novel series of compounds was identified showing low intrinsic activities and potent affinities across the 5-HT1A, 5-HT1B, and 5-HT1D receptors as well as high selectivity against the serotonin transporter. From among these compounds, 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (36) was found to combine potent in vivo activity with a strong preclinical developability profile, and on this basis it was selected as a drug candidate with the aim of assessing its potential as a fast-onset antidepressant/anxiolytic.

Synthesis and pharmacological characterization of 5-phenyl-2-[2-(1-piperidinylcarbonyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-ones: a new class of Neuropeptide S antagonists.

A new class of selective NPS antagonist was developed starting from a commercially available product identified by screening activities. Experimental NMR observations and computational experiments allowed the discovery of a new class of derivatives. 5-Phenyl-2-[2-(1-piperidinylcarbonyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-one represents a new lead compound in the NPS antagonist field.

Discovery and structure–activity relationship of a novel spirocarbamate series of NPY Y5 antagonists

A novel series of trans-8-aminomethyl-1-oxa-3-azaspiro[4.5]decan-2-one derivatives was identified with potent NPY Y5 antagonist activity. Optimization of the original lead furnished compounds 23p and 23u, which combine sub-nanomolar Y5 activity with metabolic stability, oral bioavailability, brain penetration and strong preclinical profile for development. Both compounds significantly inhibited the food intake induced by a Y5 selective agonist with minimal effective doses of 3mg/kg po.

Towards the Discovery of New Hypnotic Agents: Synthesis and Preliminary Pharmacological Evaluation of a Novel Class of Dibenzo[a,d]cycloheptene Derivatives

Sleep deprivation is well documented to result in physiologic stress and mood disorders (depression, irritability and anxiety), and sleep disturbances are among the most prevalent clinical problems and physical signs of depression. Nonspecific pharmacotherapy available for sleep disorders currently falls into four categories: GABA receptor agonists, over-the-counter antihistamines, melatonin receptor agonists and sedating antidepressants. However, benzodiazepine and non-benzodiazepine GABAA receptor agonists all share a common adverse effect profile related to the drug class, including daytime somnolence, dizziness, headache and memory impairment. Hence, there is still a medical need for the development of new drugs with improved efficacy for the treatment of sleep disorders. It has been suggested that brain histamine is involved in the regulation of the sleep/awake cycle, arousal, cognition and memory, mainly through the histamine H1 receptor, producing a reduction of sleep latency both in preclinical and clinical studies. In parallel, selective blockade of the serotonin 5-HT2A receptor has been proved in both preclinical and clinical studies to be efficacious in reducing wake after sleep onset, increasing slow-wave sleep and total sleep time, therefore, providing consolidation of sleep. On the other hand, pharmacological studies have shown that mirtazapine (1) and mianserin (2), two noradrenergic and specific serotonergic antidepressants (NaSSAs), act by blocking 5-HT2A receptors, [7] and their broad pharmacological profile is characterized by a potent H1 antagonistic activity. As part of a program aimed at discovering novel chemical entities useful for the treatment of various sleep disorders, the model compounds mirtazapine (1) and mianserin (2) were used to design novel tetracyclic derivatives (see general template 3–4 ; Figure 1). This template is characterized by the presence of a spiro junction connecting the classical tricyclic core, suitably substituted, to a fourth exocycle ring with the nitrogen atom that can either be endo (3, X = N, W = H) or exo (4, X = CH, W = NH(CH3) and N(CH3)2) with respect to that ring.