Antagonists of the human A(2A) adenosine receptor. 4. Design, synthesis, and preclinical evaluation of 7-aryltriazolo[4,5-d]pyrimidines.
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.
Gillespie
Roger J
RJ
Vernalis R&D Ltd, Winnersh, Wokingham, UK.
Bamford
Samantha J
SJ
Botting
Ruth
R
Comer
Mike
M
Denny
Sarah
S
Gaur
Suneel
S
Griffin
Michael
M
Jordan
Allan M
AM
Knight
Anthony R
AR
Lerpiniere
Joanne
J
Leonardi
Stefania
S
Lightowler
Sean
S
McAteer
Steven
S
Merrett
Angela
A
Misra
Anil
A
Padfield
Antony
A
Reece
Mark
M
Saadi
Mona
M
Selwood
Daniel L
DL
Stratton
Gemma C
GC
Surry
Dominic
D
Todd
Richard
R
Tong
Xin
X
Ruston
Vicki
V
Upton
Rebecca
R
Weiss
Scott M
SM
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
D058917:Adenosine A2 Receptor Antagonists; D000588:Amines; D001393:Azoles; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D006220:Haloperidol; C030986:pyrimidine