Synthesis and SAR of 6-substituted purine derivatives as novel selective positive inotropes.
A series of purine derivatives was prepared and examined for selective inotropic activity in vitro and in vivo. Thioether-linked derivatives were superior to their oxygen and nitrogen isosteres. Substitution of electron-withdrawing groups on the benzhydryl moiety of these agents increased potency. The best compound of the study, 17 (carsatrin), was examined further and demonstrated selective oral activity as a positive inotrope. These compounds are presumed to act by affecting the kinetics of the cardiac sodium channel by analogy to the prototypic agent DPI 201106 (1). Their high selectivity for increasing contractile force and dP/dt without affecting blood pressure or heart rate is consistent with this mechanism. Carsatrin (17) was selected as a potential development candidate.
Press
J B
JB
R.W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477.
Falotico
R
R
Hajos
Z G
ZG
Sawyers
R A
RA
Kanojia
R M
RM
Williams
L
L
Haertlein
B
B
Kauffman
J A
JA
Lakas-Weiss
C
C
Salata
J J
JJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D004285:Dogs; D005289:Ferrets; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D015122:Mercaptopurine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D015394:Molecular Structure; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship
D002316:Cardiotonic Agents; D010879:Piperazines; D011687:Purines; D015222:Sodium Channels; C078816:carsatrin; D015122:Mercaptopurine