Emiliano Castiglioni

Synthesis and pharmacological characterization of novel druglike corticotropin-releasing factor 1 antagonists.

To identify new CRF(1) receptor antagonists, an attempt to modify the bis-heterocycle moiety present in the top region of the dihydropyrrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF(1) receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic heterocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate analysis of the substitution of the pendant aryl ring, enabled to identify in vitro potent compounds showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.

Dihydropyrrole[2,3-d]pyridine derivatives as novel corticotropin-releasing factor-1 antagonists: mapping of the receptor binding pocket by in silico docking studies.

In an effort to discover novel CRF-1 receptor antagonists exhibiting improved physicochemical properties, a dihydropirrole[2,3]pyridine scaffold was designed and explored in terms of the SAR of the substitution at the pendent phenyl ring and the nature of the heterocyclic moieties present in the upper region of the molecule. Selective and potent compounds have been discovered endowed with reduced ClogP with respect to compounds known in the literature. Of particular relevance was the finding that the in vitro affinity of the series was maintained by reducing the overall lipophilicity. The results achieved by this exploration enabled the formulation of a novel hypothesis on the nature of the receptor binding pocket of this class of CRF-1 receptor antagonists, making use of in silico docking studies of the putative nonpeptidic antagonist binding site set up in house by homology modeling techniques.

Cyclopenta[d]pyrimidines and Dihydropyrrolo[2,3‐d]pyrimidines as Potent and Selective Corticotropin‐Releasing Factor 1 Receptor Antagonists

Two new classes of potent and selective CRF1 receptor antagonists are presented. Exploration of general templates 3 and 4 through modifications of the top amine and bottom phenyl substituents led to optimization of the in vitro affinity and pharmacokinetic profiles. The typical alkyl chains present in the top region of CRF1 antagonists were replaced by substituted heteroaryl moieties, leading to a dramatic improvement of the metabolic stability. This improvement was apparent when the compounds were dosed in vivo: several compounds exhibited low plasma clearance, good oral bioavailability, and high brain penetration. As a consequence of their outstanding pharmacokinetic profiles, these CRF1 antagonists, as exemplified by compound 4 fi (4‐(4‐bromo‐3‐methyl‐1H‐pyrazol‐1‐yl)‐7‐(2,4‐dichlorophenyl)‐2‐methyl‐6,7‐dihydro‐5H‐pyrrolo[2,3‐d]pyrimidine), produced a dose‐dependent “anxiolytic‐like” effect when administered orally, decreasing the vocalization of rat pups.

Heteroaryl-substituted 4-(1H-pyrazol-1-yl)-5,6-dihydro-1H-pyrrolo[2,3-d]pyrimidine derivatives as potent and selective corticotropin-releasing factor receptor-1 antagonists.

Heteroaryl-Substituted 4-(1H-pyrazol-1-yl)-5,6-dihydro-1H-pyrrolo[2,3-d]pyrimidine Derivatives as Potent and Selective CorticotropinReleasing Factor Receptor-1 Antagonists Fabio Maria Sabbatini,* Romano Di Fabio,* Yves St-Denis, Anna-Maria Capelli, Emiliano Castiglioni, Stefania Contini, Daniele Donati, Elettra Fazzolari, Gabriella Gentile, Fabrizio Micheli, Francesca Pavone, Marilisa Rinaldi, Alessandra Pasquarello, Maria Grazia Zampori, Pina Di Felice, Paola Zarantonello, Roberto Arban, Benedetta Perini, Giovanni Vitulli, Roberto Benedetti, Beatrice Oliosi, and Angela Worby

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.