title: Exploiting the pyrazolo[3,4-d]pyrimidin-4-one ring system as a useful template to obtain potent adenosine deaminase inhibitors.
abstract: A number of pyrazolo[3,4-d]pyrimidin-4-ones bearing either alkyl or arylalkyl substituents in position 2 of the nucleus were synthesized and tested for their ability to inhibit adenosine deaminase (ADA) from bovine spleen. The 2-arylalkyl derivatives exhibited excellent inhibitory activity, showing Ki values in the nanomolar/subnanomolar range. The most active compound, 1-(4-((4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-2-yl)methyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea, 14d, was tested in rats with colitis induced by 2,4-dinitrobenzenesulfonic acid to assess its efficacy to attenuate bowel inflammation. The treatment with 14d induced a significant amelioration of both systemic and intestinal inflammatory alterations in animals with experimental colitis. Docking simulations of the synthesized compounds into the ADA catalytic site were also performed to rationalize the structure-activity relationships observed and to highlight the key pharmacophoric elements of these products, thus prospectively guiding the design of novel ADA inhibitors.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno, 6, 56126 Pisa, Italy. lamotta@farm.unipi.it
authors.forename: Concettina
authors.initials: C
authors.lastname: La Motta
authors.forename: Stefania
authors.initials: S
authors.lastname: Sartini
authors.forename: Laura
authors.initials: L
authors.lastname: Mugnaini
authors.forename: Silvia
authors.initials: S
authors.lastname: Salerno
authors.forename: Francesca
authors.initials: F
authors.lastname: Simorini
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Marini
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Luca
authors.initials: L
authors.lastname: Antonioli
authors.forename: Matteo
authors.initials: M
authors.lastname: Fornai
authors.forename: Corrado
authors.initials: C
authors.lastname: Blandizzi
authors.forename: Mario
authors.initials: M
authors.lastname: Del Tacca
mesh_terms: D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D020134:Catalytic Domain; D003092:Colitis / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D058892:Adenosine Deaminase Inhibitors; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011725:Pyridines; C447480:pyrazolo(3,4-b)pyridine