Fabio Maria Sabbatini

GSK1614343, a novel ghrelin receptor antagonist, produces an unexpected increase of food intake and body weight in rodents and dogs.

Ghrelin is a 28-amino-acid polypeptide expressed in the stomach and hypothalamus that stimulates GH secretion, increases food intake (FI) and promotes body weight (BW) gain most likely via activation of the growth hormone secretagogue receptor type 1a (GHSR1a). GSK1614343 is a novel selective and potent GHSR antagonist with no partial agonist properties, recently characterized as GH secretion inhibitor by Sabbatini et al. [Chem Med Chem 2010;5:1450–1455]. In the present study, GSK1614343 (10 mg/kg) was not able to antagonize ghrelin-induced food consumption in rat, but unexpectedly stimulated FI and BW gain in both rats and dogs, a profile associated with decreased ghrelin plasma level. Interestingly, GSK1614343 selectively reduced the pro-opiomelanocortin mRNA levels in rat hypothalami chronically treated with the compound. To better understand the observed effects, we administered GSK1614343 (30 mg/kg) to Ghsr null mice and measured body mass components (fat, lean and free fluid) by using a NMR spectrometer. The increases of FI and BW were abolished in Ghsr null mice, while fat and lean masses increased in wild-type mice. Taken together, these results indicate that the orexigenic effect of GSK1614343 is mediated by GHSR1a and that the weight gain could be attributed to the increase of both adiposity and muscle mass, but not to fluid retention. The observed dissociation between effects on GH secretion and effects on FI/BW is inconsistent with a simple hormone-receptor model, suggesting unknown underlying regulations of the ghrelin system whose understanding require further investigation.

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.

Synthesis and pharmacological characterisation of 2,4-Dicarboxy-pyrroles as selective non-Competitive mGluR1 antagonists

Metabotropic glutamate receptors (mGluRs) are an unusual family of G-protein coupled receptor (GPCR), and are characterised by a large extracellular N-terminal domain that contains the glutamate binding site. We have identified a new class of non-competitive metabotropic glutamate receptor 1 (mGluR1) antagonists, 2,4-dicarboxy-pyrroles which are endowed with nanomolar potency. They interact within the 7 transmembrane (7TM) domain of the receptor and show antinociceptive properties when tested in a number of different animal models.

2,4-Dicarboxy-pyrroles as selective non-competitive mGluR1 antagonists: further characterization of 3,5-dimethyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-trimethyl-propyl) ester and structure-activity relationships.

Following the disclosure of 3,5-dimethyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-trimethyl-propyl) ester [3,5-dimethyl PPP] as a potent and selective mGluR1 non-competitive antagonist, we report here further in vivo characterization of this important tool and disclose the investigation of the C-5 position, which led to very potent compounds.

Highly Diastereoselective Synthesis of 4-N-Methylformamidino Trinem (GV129606), a Potent Antibacterial Agent

Abstract In this paper a highly diastereoselective synthesis of 4-N-methylformamidino trinem 3 is reported. The route offers advantages compared to that previously used, i.e. the higher overall yield, the robustness, the avoidance of toxic reagents. Most of the compounds were isolated by precipitation, therefore reducing the number of chromatographic separations. The efficient conversion of 4-N-methylamino trinem 11 into GV129606 3, was obtained by a new methodology in which a scavenger resin was used. The route presented in this paper allowed the preparation of the material required for early development studies and demonstrates the versatility of cyclohexenyl azetidinone 12 in the synthesis of 4-substituted trinems.

Metabotropic glutamate receptors: potential therapeutic applications of recently disclosed new chemical entities

Glutamate is the main excitatory neurotransmitter in the mammalian CNS and it exerts its action through ionotropic and metabotropic receptors. Whereas ion channels have been heavily exploited in the recent past, metabotropic glutamate receptor (mGlu) research has been hampered by the lack of potent and selective molecules with ‘drug-like’ structures. A new wave of ligands has recently been disclosed by a number of pharmaceutical companies highlighting the great interest around these potential therapeutic targets. This review endeavours to provide the reader with an updated and detailed panorama of the patent literature of this exciting field, also tackling non-competitive and allosteric modulators. Those skilled in the art know that it is quite difficult to extract structure–activity relationship (SAR) information from a patent or to draw ‘definitive’ conclusions on a compound if biological data are not specifically provided. Accordingly, the main aim of this review will be to provide the reader with the most relevant information available and to report the structures of the newly unveiled chemical entities. Other very interesting compounds recently disclosed in the primary literature will not be exhaustively covered here, but they are surely worth a further check in the available literature databases, a few examples will be mentioned only where a novel therapeutic area is disclosed or if major insights are provided.

Discovery Process and Characterization of Novel Carbohydrazide Derivatives as Potent and Selective GHSR1a Antagonists

Fabio Maria Sabbatini,* Romano Di Fabio,* Mauro Corsi, Paolo Cavanni, Steve M. Bromidge, Yves St-Denis, Lucilla D’Adamo, Stefania Contini, Marilisa Rinaldi, Sebastien Guery, Chiara Savoia, Claudia Mundi, Benedetta Perini, Andrew J. Carpenter, Giovanna Dal Forno, Federico Faggioni, Michela Tessari, Francesca Pavone, Carla Di Francesco, Alberto Buson, Mario Mattioli, Elisabetta Perdona’, and Sergio Melotto

Benzoazepine derivative as potent antagonists of the glycine binding site associated to the NMDA receptor

A series of benzoazepine derivatives, bearing suitable substituents at the C-3 position, was designed and evaluated by superimposition with the pharmacophore model of the glycine binding site. To fully explore the SAR of this class of compounds and to allow the preparation of new different compounds at the C-3 position, appropriate synthetic routes were set up. The benzoazepines were evaluated in terms of in vitro affinity using [3H]glycine binding assay and in vivo potency by inhibition of convulsions induced by N-methyl-D-aspartate (NMDA) in mice. This further analysis confirmed the preliminary results previously reported and that compound 27 is the most promising compound (Ki=32 nM, ED(50)=0.09 mg/kg, i.v.) in this series. Significant neuroprotective effect was observed after both pre- and post-ischaemia administration in the MCAo model. In particular, after post-ischaemia administration, it was found to be still effective when the administration was delayed up to 6 h after occlusion of the middle cerebral artery.

Azabicyclo[3.1.0]hexane‐1‐carbohydrazides as Potent and Selective GHSR1a Ligands Presenting a Specific in vivo Behavior

Azabicyclo[3.1.0]hexane-1-carbohydrazides as Potent and Selective GHSR1a Ligands Presenting a Specific in vivo Behavior Fabio Maria Sabbatini,* Sergio Melotto, Giovanni Bernasconi, Steve M. Bromidge, Lucilla D’Adamo, Marilisa Rinaldi, Chiara Savoia, Claudia Mundi, Carla Di Francesco, Laura Zonzini, Vivian J. A. Costantini, Benedetta Perini, Enzo Valerio, Alfonso Pozzan, Elisabetta Perdon , Filippo Visentini, Mauro Corsi, and Romano Di Fabio*

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.