Daniele Andreotti

GSK2578215A; a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor.

Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for some forms of Parkinsons disease. Here we report the discovery and characterization of 2-arylmethyloxy-5-subtitutent-N-arylbenzamides with potent LRRK2 activities exemplified by GSK2578215A which exhibits biochemical IC(50)s of around 10 nM against both wild-type LRRK2 and the G2019S mutant. GSK2578215A exhibits exceptionally high selectivity for LRRK2 across the kinome, substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.3-1.0 μM in cells and in mouse spleen and kidney, but not in brain, following intraperitoneal injection of 100mg/kg.

6-(3,4-Dichlorophenyl)-1-[(Methyloxy)methyl]-3-azabicyclo[4.1.0]heptane: A New Potent and Selective Triple Reuptake Inhibitor

A pharmacophore model for triple reuptake inhibitors and the new class of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes were recently reported. Further investigation in this area led to the identification of a new series of potent and selective triple reuptake inhibitors endowed with good developability characteristics. Excellent bioavailability and brain penetration are associated with this series of 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanes together with high in vitro potency and selectivity at SERT, NET, and DAT. In vivo microdialysis experiments in different animal models and receptor occupancy studies in rat confirmed that derivative 17 showed an appropriate profile to guarantee further progression of the compound.

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.

Discovery of N-[(2S)-5-(6-Fluoro-3-Pyridinyl)-2,3-Dihydro-1H-Inden-2-Yl]-2-Propanesulfonamide, a Novel Clinical Ampa Receptor Positive Modulator.

A series of AMPA receptor positive allosteric modulators has been optimized from poorly penetrant leads to identify molecules with excellent preclinical pharmacokinetics and CNS penetration. These discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic profile across preclinical species, which is well tolerated and is also orally bioavailable in humans.

A specific and direct comparison of the trifluoromethyl and pentafluoro sulfanyl groups on the selective dopamine D3 antagonist 3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-phenyl-3-azabicyclo[3.1.0]-hexane template

A direct and specific comparison of a trifluoromethyl group with the corresponding pentafluorosulfanyl group is made in terms of primary affinity and pharmacokinetic properties.

Synthesis and antibacterial activity of 4- and 8-methoxy trinems

Abstract The synthesis of all the isomers of 8-methoxy-(9 S ,10 S ,12 R )-10-(1-hydroxyethyl)-11-oxo-1-azatricyclo-[7.2.0.0 3,8 ]-undec-2-ene-carboxylates 2 and 4-methoxy-(9 R ,10 S ,12 R )-10-(1-hydroxyethyl)-11-oxo-1-azatricyclo-[7.2.0.0 3,8 ]-undec-2-ene-carboxylates 3 is described. The biological data obtained indicated that the (4 S ,8 S )-4-methoxy derivative ( 3b ) is the best compound in terms of microbiological activity, breadth of spectrum of action and stability to hydrolytic enzymes, namely β-lactamases.

The squalestatins: Cleavage of the bicyclic core via the novel 2,8,9-trioxabicyclo[3.3.1]nonane ring system

Abstract Squalestatin 1 was converted into the γ-lactone analogue 5 , via hydrolysis of the novel ortho ester anhydride 3 , and thence into the acyclic derivative 8 .

Synthesis and biological evaluation of 4-alkoxy substituted trinems. Part I

Abstract Synthesis of new 4-alkoxy substituted trinems 4, 5, 6, 7 and 8 together with their antibacterial profiles compared to imipenem and GV104326 ( 2 ) are described. The good antibacterial profile observed for derivatives 4–7 encouraged further exploration of these derivatives.

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.

SYNTHESIS AND BIOLOGICAL EVALUATION OF 4-ALKOXYSUBSTITUTED TRINEMS. PART II

Abstract The synthesis and the microbiological evaluation of a novel series of substituted tricyclic β-lactam derivatives (trinems, former named tribactams) is reported. Suitable basic groups were introduced within the key C-4 side chain with the aim of improving the antibacterial activity of this class of new antibiotics to Pseudomonas spp.. Among the different compounds prepared, basic derivatives 2 and 3 showed improved activity with respect to GV 104326 1 against these highly resistant strains.