Discovery of novel 2,8-diazaspiro[4.5]decanes as orally active glycoprotein IIb-IIIa antagonists.
In our efforts to develop orally active GPIIb-IIIa antagonists with improved pharmaceutical properties, we have utilized a novel 2,8-diazaspiro[4.5]decane scaffold as a template. We describe here our investigation of a variety of templates including spiropiperidinyl-gamma-lactams, spiropiperidinylimide, spiropiperidinylureas, and spiropiperidinylhydantoins. With the appropriate acidic and basic pharmacophores in place, each template yielded analogues with potent GPIIb-IIIa inhibitory activity. One of the compounds, 59 (CT50787), was also used to demonstrate for the first time the use of a pharmacological agent which is alphaIIbbeta3 specific to display biological activity in a lower species such as mouse and to extend bleeding times. Evaluation of the pharmacokinetic properties of selected compounds from each series in rat, dog, and cynomolgus monkey has led to the identification of 22 (CT51464), a double prodrug, with excellent pharmacokinetic properties. It exhibited good pharmacokinetic profile across species (F% = 33 (Cyno), 73 (dog), 22 (rat); t(1/2)(beta)() = 14.2 h (Cyno), 8.97 h (dog), 1.81 h (rat)). The biologically active form, 23 (CT50728), displayed inhibition of platelet aggregation in platelet rich plasma (PRP) with an IC(50) value of 53 nM in citrate buffer, 110 nM in PPACK anticoagulated PRP, and 4 nM in solid-phase GPIIb-IIIa competition binding assay (ELISA). Both 23 and 22 were stable in human liver microsomes, did not inhibit the P450 3A4 isozyme, and had low protein binding (18.22% for 23) and a desirable log P (0.45 +/- 0.06 for 22, and -0.91 +/- 0.32 for 23). It is predicted that the high oral bioavailability for these compounds in multiple species should translate into lower intra- and intersubject variability in man. The long plasma half-life of the lead is consistent with once or twice daily administration for chronic therapy. Analogue 22 (CT51464) thus appears to be a promising oral GPIIb-IIIa inhibitor with significantly improved pharmacokinetic properties over the previously described clinical candidates and may be found useful in the treatment of arterial occlusive disorders.
Mehrotra
Mukund M
MM
Millennium Pharmaceuticals Inc., 256 E. Grand Avenue, South San Francisco, CA 94080, USA. mukund_mehotra@hotmail.com
Heath
Julie A
JA
Smyth
Mark S
MS
Pandey
Anjali
A
Rose
Jack W
JW
Seroogy
Joseph M
JM
Volkots
Deborah L
DL
Nannizzi-Alaimo
Lisa
L
Park
Gary L
GL
Lambing
Joseph L
JL
Hollenbach
Stanley J
SJ
Scarborough
Robert M
RM
D000284:Administration, Oral; D000473:Alkanes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D001682:Biological Availability; D001760:Bleeding Time; D004285:Dogs; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D006898:Hydroxylamines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D007769:Lactams / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D051379:Mice; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
C485112:3-((2-(4-(N-hydroxycarbamimidoyl)phenyl)-1-oxo-2,8-diazaspiro(4,5)decane-8-carbonyl)amino)propionic acid ethyl ester; D000473:Alkanes; D001372:Aza Compounds; D006827:Hydantoins; D006898:Hydroxylamines; D007769:Lactams; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011355:Prodrugs; D013141:Spiro Compounds; D014508:Urea