title: Synthesis and SAR study of novel tricyclic pyrazoles as potent phosphodiesterase 10A inhibitors.
abstract: Novel pyrazolo[5,1-f][1,6]naphthyridines, pyrazolo[5,1-a][2,6]naphthyridines, pyrazolo[5,1-a][2,7]naphthyridines and pyrazolo[5,1-a]isoquinolines phenylimidazole/benzimidazole ethylene-linked were designed and synthesized for PDE10A interaction. An AgOTf and proline-cocatalyzed multicomponent methodology based on use of o-alkynylaldehydes, tosylhydrazide and ketones was developed and proved to be a convenient route for assembly of most of the novel tricyclic pyrazoles synthesized. Pyrazolo[5,1-f][1,6]naphthyridine 43 and 59, pyrazolo[5,1-a][2,6]naphthyridine 66, and pyrazolo[5,1-a][2,7]naphthyridine 42 showed the highest affinity for PDE10A enzyme (IC50 = 40, 42, 40, 55 nM, respectively).
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Dore
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy. Electronic address: asproni@uniss.it.
authors.forename: Battistina
authors.initials: B
authors.lastname: Asproni
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Scampuddu
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Gerard Aime
authors.initials: GA
authors.lastname: Pinna
authors.affiliation: H. Lundbeck A/S, Department of Molecular Pharmacology, 9 Ottiliavej, DK-2500 Valby, Denmark.
authors.forename: Claus Tornby
authors.initials: CT
authors.lastname: Christoffersen
authors.affiliation: H. Lundbeck A/S, Discovery Chemistry and DMPK, 9 Ottiliavej, DK-2500 Valby, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Langgård
authors.affiliation: H. Lundbeck A/S, Discovery Chemistry and DMPK, 9 Ottiliavej, DK-2500 Valby, Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Kehler
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
keywords: PDE10A inhibition; Structure–activity relationships; Tricyclic pyrazoles