title: Antagonists of the human A(2A) adenosine receptor. 4. Design, synthesis, and preclinical evaluation of 7-aryltriazolo[4,5-d]pyrimidines.
abstract: Antagonism of the human A(2A) receptor has been implicated as a point of therapeutic intervention in the alleviation of the symptoms associated with Parkinson's disease. This is thought to occur, at least in part, by increasing the sensitivity of the dopaminergic neurons to the residual, depleted levels of striatal dopamine. We herein describe a novel series of functionalized triazolo[4,5-d]pyrimidine derivatives that display functional antagonism of the A(2A) receptor. Optimization of these compounds has resulted in improvements in potency, selectivity, and the pharmacokinetic properties of key derivatives. These efforts have led to the discovery of 60 (V2006/BIIB014), which demonstrates strong oral activity in commonly used models of Parkinson's disease. Furthermore, this derivative has shown excellent preclinical pharmacokinetics and has successfully completed phase I clinical studies. This compound is presently undergoing further clinical evaluation in collaboration with Biogen Idec.
authors.affiliation: Vernalis R&D Ltd, Winnersh, Wokingham, UK.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Gillespie
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Bamford
authors.forename: Ruth
authors.initials: R
authors.lastname: Botting
authors.forename: Mike
authors.initials: M
authors.lastname: Comer
authors.forename: Sarah
authors.initials: S
authors.lastname: Denny
authors.forename: Suneel
authors.initials: S
authors.lastname: Gaur
authors.forename: Michael
authors.initials: M
authors.lastname: Griffin
authors.forename: Allan M
authors.initials: AM
authors.lastname: Jordan
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Knight
authors.forename: Joanne
authors.initials: J
authors.lastname: Lerpiniere
authors.forename: Stefania
authors.initials: S
authors.lastname: Leonardi
authors.forename: Sean
authors.initials: S
authors.lastname: Lightowler
authors.forename: Steven
authors.initials: S
authors.lastname: McAteer
authors.forename: Angela
authors.initials: A
authors.lastname: Merrett
authors.forename: Anil
authors.initials: A
authors.lastname: Misra
authors.forename: Antony
authors.initials: A
authors.lastname: Padfield
authors.forename: Mark
authors.initials: M
authors.lastname: Reece
authors.forename: Mona
authors.initials: M
authors.lastname: Saadi
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Selwood
authors.forename: Gemma C
authors.initials: GC
authors.lastname: Stratton
authors.forename: Dominic
authors.initials: D
authors.lastname: Surry
authors.forename: Richard
authors.initials: R
authors.lastname: Todd
authors.forename: Xin
authors.initials: X
authors.lastname: Tong
authors.forename: Vicki
authors.initials: V
authors.lastname: Ruston
authors.forename: Rebecca
authors.initials: R
authors.lastname: Upton
authors.forename: Scott M
authors.initials: SM
authors.lastname: Weiss
mesh_terms: D058917:Adenosine A2 Receptor Antagonists; D000588:Amines / Q000737:chemistry; D000818:Animals; D001393:Azoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D020233:Gait Disorders, Neurologic / Q000139:chemically induced / Q000188:drug therapy; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D043705:Receptor, Adenosine A2A / Q000145:classification / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D000588:Amines; D001393:Azoles; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D006220:Haloperidol; C030986:pyrimidine