A novel approach to dual-acting thromboxane receptor antagonist/synthase inhibitors based on the link of 1,3-dioxane-thromboxane receptor antagonists and -thromboxane synthase inhibitors.
A new class of dual-acting racemic thromboxane receptor antagonist/thromboxane synthase inhibitors is reported, based on the novel approach of linking the known thromboxane synthase inhibitors (TXSI) dazoxiben (2) or isbogrel (11) (separately) to thromboxane receptor antagonists (TXRA) from the 1,3-dioxane series, such as ICI 192605 (10). Dual activity was observed in vitro with inhibition of human microsomal thromboxane synthase in the range IC50 = 0.01-1.0 microM and receptor antagonist activity by inhibition of U46619-induced human platelet aggregation in the range pA2 = 5.5-7.0. The in vitro results also showed that very large groups could be tolerated at the selected substitution positions of the TXRA and TXSI components. Oral activity was observed in ex vivo tests in both rats and dogs at a dose of 10 mg/kg. Thus, (E)-7-[4-[[4-[(2SR,4SR,5RS)-5-[(Z)-5-carboxypent -2-enyl]-4-(2- hydroxyphenyl)-1,3-dioxan-2-yl]-benzyl]oxy]phenyl]-7-(3-pyridyl)he pt-6- enoic acid (110) was both an antagonist (pA2 = 6.7) and a synthase inhibitor (IC50 = 0.02 microM). On oral dosing (10 mg/kg) to rats and dogs, 110 showed significant TXRA activity [concentration ratio > 64 (rat, 3 h) and > 59 +/- 11.3 (dog, 2 h) vs ex vivo U46619-induced platelet aggregation]. Inhibition of thromboxane synthase at the respective time points in these experiments was 81 +/- 4.4% (rat) and 69 +/- 4.8% (dog).
Ackerley
N
N
Cardiovascular and Metabolism Department, ZENECA Pharmaceuticals, Alderly Park, Macclesfield, Cheshire, U.K.
Brewster
A G
AG
Brown
G R
GR
Clarke
D S
DS
Foubister
A J
AJ
Griffin
S J
SJ
Hudson
J A
JA
Smithers
M J
MJ
Whittamore
P R
PR
D000818:Animals; D004146:Dioxanes / Q000737:chemistry* / Q000494:pharmacology; D004285:Dogs; D006801:Humans; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry
C093617:7-(4-((4-(5-(5-carboxypent-2-enyl)-4-(2-hydroxyphenyl)-1,3-dioxan-2-yl)benzyl)oxy)phenyl)-7-(3-pyridyl)hept-6-enoic acid; D004146:Dioxanes; D010975:Platelet Aggregation Inhibitors; D017482:Receptors, Thromboxane; D013930:Thromboxane-A Synthase; C025223:1,4-dioxane