Description

In the 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. It describes here the investigation of a variety of templates including spiropiperidinyl-γ -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 αIIbβ3 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 (Fpercent = 33 (Cyno), 73 (dog), 22 (rat); t1/2β = 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 IC50 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 (18.22percent 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.

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 2,8-Diazaspiro[4.5]decan-3-one (561314-57-6) Specifications

CAS	561314-57-6
CAS Min %	95.0
CAS Max %	98.0
MDL Number	MFCD11044206
InChI Key	ASPBBYVNTMIKLA-UHFFFAOYSA-N
Chemical Name or Material	2,8-Diazaspiro[4.5]decan-3-one
Infrared Spectrum	Authentic
Physical Form	N/A
Packaging	Glass bottle
Molecular Formula	C8H14N2O
Molecular Weight (g/mol)	154.212
SMILES	C1CNCCC12CC(=O)NC2
Color	yellow
Melting Point	N/A
Assay	≧98%

2,8-Diazaspiro[4.5]decan-3-one (561314-57-6) Safety and Handling

2,8-Diazaspiro[4.5]decan-3-one Hazard description:

w Harmful if swallowed

w Causes serious eye irritation.

w Causes skin irritation.

w May cause respiratory irritation.

w Avoid breathing dust/fume/gas/mist/vapors/spray.

561314-57-6 Precautionary statement:

w Avoid breathing dust/fume/gas/mist/vapours/spray.

w Wear protective gloves and eye/face protection.

w IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.

WARNING: The information provided on this web site was developed in compliance with European Union (EU) regulations and is correct to the best of our knowledge, information and belief at the date of its publication. The information given is designed only as a guide for safe handling and use. It is not to be considered as either a warranty or quality specification.

Articles

Discovery of Novel 2,8-Diazaspiro[4.5]decanes as Orally Active Glycoprotein IIb-IIIa AntagonistsMehrotra,

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… Journal of Medicinal Chemistry 2004.

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