Inhibitors of blood platelet cAMP phosphodiesterase. 4. Structural variation of the side-chain terminus of water-soluble 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives.
1-(Cyclohexylmethyl)-4-[4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b] quinolin-7-yl)oxy]-1-oxobutyl]piperazine (2) was previously identified as a potent, water-soluble inhibitor of human blood platelet cAMP phosphodiesterase and of induced aggregation in vitro that demonstrated effective antithrombotic activity in animal models of thrombosis. Although 2 exhibited 25% oral bioavailability in rats, pharmacokinetic studies conducted in monkeys revealed that the parent compound was less than 5% bioavailable, the result of extensive first-pass biotransformation in the liver. In an effort to identify potent platelet aggregation inhibitors with enhanced metabolic stability, the side-chain amide moiety of 2 was replaced with chemically more stable urea (6a-s), sulfonamide (13a-m), sulfone (19a-r), and tetrazole (23a-s) moieties. Many representatives from each of these structural types effectively combined potent inhibition of ADP-induced human platelet aggregation in vitro with excellent aqueous solubility, and several are superior to 2. Within each series, the N-(cyclohexylmethyl)-, N-(2-ethylbutyl)-, N-benzyl-, and N-(4-fluorobenzyl)-substituted derivatives were evaluated for in vitro metabolic stability by incubating with the S-9 fraction of monkey liver for 2 h, and the extent of biotransformation was compared with that of the prototype 2. The sulfone 19e and the tetrazoles 23e, 23g, 23j, and 23q were significantly more stable than 2 under these conditions, and 19e and 23e were selected for evaluation in vivo. Tetrazole 23e exhibited 72% bioavailability following ip administration to rats compared with 35% bioavailability for 2 and 19e under the same conditions. However, the oral bioavailability of 19e and 23e in the rat was estimated to be only 3%, suggesting that 19e and 23e are less readily absorbed from the gastrointestinal tract than 2.
Meanwell
N A
NA
Division of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492.
Hewawasam
P
P
Thomas
J A
JA
Wright
J J
JJ
Russell
J W
JW
Gamberdella
M
M
Goldenberg
H J
HJ
Seiler
S M
SM
Zavoico
G B
GB
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000097:blood; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology*; D002522:Chlorocebus aethiops; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis*; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology; D013450:Sulfones / Q000138:chemical synthesis / Q000494:pharmacology; D013777:Tetrazoles / Q000138:chemical synthesis / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D014867:Water
D007093:Imidazoles; D010975:Platelet Aggregation Inhibitors; D015363:Quinolones; D013449:Sulfonamides; D013450:Sulfones; D013777:Tetrazoles; D014867:Water; D000244:Adenosine Diphosphate; D014508:Urea; D015105:3',5'-Cyclic-AMP Phosphodiesterases