Investigation on the antiplatelet activity of pyrrolo[3,2-c]pyridine-containing compounds.
A series of 4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridines (THPPs), mostly C(2)-substituted derivatives, and some 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles (THPIs) were synthesized and tested in-vitro for their ability to inhibit aggregation of human platelet-rich plasma (PRP) induced by adenosine 5'-diphosphate (ADP) and adrenaline (epinephrine). 5-Benzyl THPP (3), 2-(benzylamino)methyl THPP (5f) and 2-ethyl THPI (6) moderately and dose-dependently inhibited platelet aggregation induced by adrenaline and, to a lesser extent, by ADP. These compounds inhibited the second phase of the PRP aggregation triggered by adrenaline, which largely depends upon thromboxane A(2) production and ADP release. In the adrenaline stimulated aggregation, the THPI derivative 6 was found to be nearly equipotent with aspirin, their IC50 values (concentration effecting 50% inhibition of aggregation) being 90 and 60 microM, respectively. A relation between activity and calculated octanol-water partition coefficient suggested that a log P value around 2.5 should be the optimal lipophilicity value for the activity of THPP-containing compounds.
Voskressensky
Leonid G
LG
Organic Chemistry Department, Russian Peoples' Friendship University, 6, Miklukho-Maklaia St, Moscow, 117198 Russia.
de Candia
Modesto
M
Carotti
Andrea
A
Borisova
Tatiana N
TN
Kulikova
Larisa N
LN
Varlamov
Alexey V
AV
Altomare
Cosimo
C
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000328:Adult; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008875:Middle Aged; D009391:Nephelometry and Turbidimetry; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D011758:Pyrroles; C475261:pyrrolo(3,2-c)pyridine; D000244:Adenosine Diphosphate; D004837:Epinephrine