In vivo characterization of a dual adenosine A2A/A1 receptor antagonist in animal models of Parkinson's disease.
The in vivo characterization of a dual adenosine A(2A)/A(1) receptor antagonist in several animal models of Parkinson's disease is described. Discovery and scale-up syntheses of compound 1 are described in detail, highlighting optimization steps that increased the overall yield of 1 from 10.0% to 30.5%. Compound 1 is a potent A(2A)/A(1) receptor antagonist in vitro (A(2A) K(i) = 4.1 nM; A(1) K(i) = 17.0 nM) that has excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse model of reserpine-induced akinesia, rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation, and MPTP-treated non-human primate model.
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Welsh and McKean Roads, P.O. Box 776, Spring House, Pennsylvania 19477, USA. bshook@its.jnj.com
Brian C
BC
Shook
Stefanie
S
Rassnick
Melville C
MC
Osborne
Scott
S
Davis
Lori
L
Westover
Jamie
J
Boulet
Daniel
D
Hall
Kenneth C
KC
Rupert
Geoffrey R
GR
Heintzelman
Kristin
K
Hansen
Devraj
D
Chakravarty
James L
JL
Bullington
Ronald
R
Russell
Shawn
S
Branum
Kenneth M
KM
Wells
Sandra
S
Damon
Scott
S
Youells
Xun
X
Li
Derek A
DA
Beauchamp
David
D
Palmer
Mayra
M
Reyes
Keith
K
Demarest
Yuting
Y
Tang
Kenneth
K
Rhodes
Paul F
PF
Jackson
D058916:Adenosine A1 Receptor Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002144:Callithrix; D004195:Disease Models, Animal; D005260:Female; D007192:Indenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010300:Parkinson Disease / Q000378:metabolism*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000502:physiology*
C554510:2-amino-4-phenyl-8-(pyrrolidin-1-ylmethyl)-5H-indeno(1,2-d)pyrimidin-5-one; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D007192:Indenes; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A