Exploiting the pyrazolo[3,4-d]pyrimidin-4-one ring system as a useful template to obtain potent adenosine deaminase inhibitors.
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.
La Motta
Concettina
C
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno, 6, 56126 Pisa, Italy. lamotta@farm.unipi.it
Sartini
Stefania
S
Mugnaini
Laura
L
Salerno
Silvia
S
Simorini
Francesca
F
Taliani
Sabrina
S
Marini
Anna Maria
AM
Da Settimo
Federico
F
Lavecchia
Antonio
A
Novellino
Ettore
E
Antonioli
Luca
L
Fornai
Matteo
M
Blandizzi
Corrado
C
Del Tacca
Mario
M
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
D058892:Adenosine Deaminase Inhibitors; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011725:Pyridines; C447480:pyrazolo(3,4-b)pyridine