Inhibitors of blood platelet cAMP phosphodiesterase. 2. Structure-activity relationships associated with 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-ones substituted with functionalized side chains.
A series of 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives, substituted at the 7-position with functionalized side chains, was synthesized and evaluated as inhibitors of human blood platelet cAMP phosphodiesterase (PDE) as well as ADP- and collagen-induced platelet aggregation, in vitro. Structural modifications focused on variation of the side-chain terminus, side-chain length, and side-chain connecting atom. Functionality incorporated at the side-chain terminus included carboxylic acid, ester and amide, alcohol, acetate, nitrile, tetrazole, and phenyl sulfone moieties. cAMP PDE inhibitory potency varied and was dependent upon the side-chain terminus and its relationship with the heterocyclic nucleus. Methylation at N-1 or N-3 of the heterocycle diminished cAMP PDE inhibitory potency. Several representatives of this structural class demonstrated potent inhibition of ADP- and collagen-induced blood platelet aggregation and were half-maximally effective at low nanomolar concentrations. Amides 13d, 13f, 13h, 13k, 13m, and 13w are substantially more potent than relatively simply substituted compounds. However, platelet inhibitory properties did not always correlate with cAMP PDE inhibition across the series, probably due to variations in membrane permeability. Several compounds inhibited platelet aggregation measured ex vivo following oral administration to rats. Ester 11b, acid 12b, amide 13d, and sulfone 29c protected against thrombus formation in two different animal models following oral dosing and were found to be superior to anagrelide (2) and BMY 20844 (5). However, ester 11b and acid 12b demonstrated a unique pharmacological profile since they did not significantly affect hemodynamic parameters in dogs at doses 100-fold higher than that required for complete prevention of experimentally induced vessel occlusion in a dog model of thrombosis.
Meanwell
N A
NA
Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492.
Pearce
B C
BC
Roth
H R
HR
Smith
E C
EC
Wedding
D L
DL
Wright
J J
JJ
Buchanan
J O
JO
Baryla
U M
UM
Gamberdella
M
M
Gillespie
E
E
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology*; D004285:Dogs; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D008745:Methylation; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship
D007093:Imidazoles; D010975:Platelet Aggregation Inhibitors; D015363:Quinolones; D015105:3',5'-Cyclic-AMP Phosphodiesterases