Antagonists of the human A(2A) receptor. Part 6: Further optimization of pyrimidine-4-carboxamides.
Antagonists of the human A(2A) receptor have been reported to have potential therapeutic benefit in the alleviation of the symptoms associated with neurodegenerative movement disorders such as Parkinson's disease. As part of our efforts to discover potent and selective antagonists of this receptor, we herein describe the detailed optimization and structure-activity relationships of a series of pyrimidine-4-carboxamides. These optimized derivatives display desirable physiochemical and pharmacokinetic profiles, which have led to promising oral activity in clinically relevant models of Parkinson's disease.
Gillespie
Roger J
RJ
Department of Chemistry, Vernalis (R&D) Ltd, 613 Reading Road, Winnersh, Wokingham RG41 5UA, UK.
Bamford
Samantha J
SJ
Clay
Alex
A
Gaur
Suneel
S
Haymes
Tim
T
Jackson
Philip S
PS
Jordan
Allan M
AM
Klenke
Burkhard
B
Leonardi
Stefania
S
Liu
Jeanette
J
Mansell
Howard L
HL
Ng
Sean
S
Saadi
Mona
M
Simmonite
Heather
H
Stratton
Gemma C
GC
Todd
Richard S
RS
Williamson
Douglas S
DS
Yule
Ian A
IA
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D006801:Humans; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D010300:Parkinson Disease / Q000188:drug therapy*; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013329:Structure-Activity Relationship
D058917:Adenosine A2 Receptor Antagonists; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A