New platelet fibrinogen receptor glycoprotein IIb-IIIa antagonists: orally active series of N-alkylated amidines with a 6,6-bicyclic template.
The design, synthesis, and pharmacological evaluation of (S)-(-)-ethyl [6-[4-(morpholinoformimidoyl)benzamido]-3, 4-dihydro-2H-1-benzopyran-3-yl]acetate hydrochloride ((S)-4.HCl, MS-180), an orally active glycoprotein IIb-IIIa (GPIIb-IIIa) antagonist, are reported. Pharmacophore mapping of amidino and carboxyl groups of already known GPIIb-IIIa antagonists led to the synthesis of nine amidino acids containing 6,6-bicyclic ring skeletons (10a-i). Among them, the compounds 10a,c,e having an amide bond and 1,2,3,4-tetrahydronaphthalene or 3, 4-dihydro-2H-1-benzopyran skeleton showed marked inhibitions with IC50 values of 46-57 nM in human platelet aggregation assay in vitro, but low oral activities. N-Alkylation of the amidino group coupled with the ester prodrug approach afforded MS-180 ((S)-4.HCl), which generates in vivo the corresponding carboxylic acid (S)-3 as an active species. In vitro, (S)-3 inhibited ADP-induced aggregation of guinea pig, dog, and human platelets (IC50 = 110, 253, and 35 nM, respectively) and inhibited the binding of fibrinogen to immobilized GPIIb-IIIa of human platelets (IC50 = 0.12 nM). After oral administration of MS-180 ((S)-4.HCl) to fasted beagle dog, ex vivo inhibition of platelet aggregation was observed. The maximal inhibitions were observed 2-4 h after dosing with dose dependency (60% inhibition at a dose of 1 mg/kg, 85% at 3 mg/kg, and 100% at 10 mg/kg, respectively) and the extent of the inhibitions paralleled the plasma concentration of the active species (S)-3. On the basis of these studies, we selected MS-180 ((S)-4.HCl) as a candidate for clinical evaluation as a drug for the treatment and prevention of thrombosis in patients.
Okumura
K
K
Institute of Biological Science, Mitsui Pharmaceuticals Inc., 1900-1, Togo, Mobara-shi, Chiba 297-0017, Japan.
Shimazaki
T
T
Aoki
Y
Y
Yamashita
H
H
Tanaka
E
E
Banba
S
S
Yazawa
K
K
Kibayashi
K
K
Banno
H
H
D000085:Acetates / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D018360:Crystallography, X-Ray; D004285:Dogs; D005340:Fibrinogen / Q000037:antagonists & inhibitors / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D009025:Morpholines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000085:Acetates; C115068:MS 180; D009025:Morpholines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005340:Fibrinogen