Synthesis and cardiotonic activity of novel pyrimidine derivatives: crystallographic and quantum chemical studies.
The synthesis of ethyl or methyl 4-substituted or unsubstituted 2-(dimethylamino)-5-pyrimidinecarboxylates 10-20, which is mainly carried out by reaction of ethyl or methyl 2-[(dimethylamino)methylene]-3-oxoalkanoates with 1,1-dimethylguanidine, is described. The above esters were hydrolyzed to the relative carboxylic acids 21-30, which were decarboxylated to the corresponding 2,4-disubstituted pyrimidines 31-40. All the new synthesized pyrimidines were evaluated in spontaneously beating and electrically driven atria from reserpine-treated guinea pigs. Their effects were compared to those induced by milrinone in both atria preparations. Compound 28 (4-benzyl-2-(dimethylamino)-5-pyrimidinecarboxylic acid) was the most effective positive inotropic agent, while the corresponding methyl ester 17 reduced both the contractile force and the frequency of guinea pig atria. An antagonism toward the negative influence exerted by endogenous adenosine on the heart seems to be involved in the contractile activity of compound 28. By contrast, compound 17 might be partial agonist at the purinergic inhibitory (A1) receptor. X-ray analysis carried out on 17 and 28 and molecular modeling investigations extended also to related derivatives allowed a possible rationalization between structure and inotropic activity for this series of compounds.
Dorigo
P
P
Dipartimento di Farmacologia, Università di Padova, Italy.
Fraccarollo
D
D
Santostasi
G
G
Maragno
I
I
Floreani
M
M
Borea
P A
PA
Mosti
L
L
Sansebastiano
L
L
Fossa
P
P
Orsini
F
F
Benetollo
F
F
Bombieri
G
G
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D016275:Atrial Function; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002417:Cattle; D018360:Crystallography, X-Ray; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004558:Electric Stimulation; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D008297:Male; D020105:Milrinone; D008958:Models, Molecular; D008968:Molecular Conformation; D009200:Myocardial Contraction / Q000187:drug effects; D011728:Pyridones / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012110:Reserpine / Q000494:pharmacology; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship
C101607:4-benzyl-2-(dimethylamino)-5-pyrimidinecarboxylic acid; D002316:Cardiotonic Agents; D011728:Pyridones; D011743:Pyrimidines; C101606:methyl 4-benzyl-2-(dimethylamino)-5-pyrimidinecarboxylate; C027513:N(6)-cyclohexyladenosine; D012110:Reserpine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D020105:Milrinone; D000241:Adenosine