- Discovery of Novel 2,8-Diazaspiro[4.5]decanes as Orally Active Glycoprotein IIb-IIIa Antagonists
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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-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 (F% = 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 (18.22% 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.,Heath, Julie A.,Smyth, Mark S.,Pandey, Anjali,Rose, Jack W.,Seroogy, Joseph M.,Volkots, Deborah L.,Nannizzi-Alaimo, Lisa,Park, Gary L.,Lambing, Joseph L.,Hollenbach, Stanley J.,Scarborough, Robert M.
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p. 2037 - 2061
(2007/10/03)
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- Central cholinergic agents. III. Synthesis of 2-alkoxy-2,8-diazaspiro[4.5]decane-1,3-diones as muscarinic agonists
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A series of 2-alkoxy-2,8-diazaspiro[4.5]decane-1,3-diones and related compounds were synthesized and tested for muscarinic receptor binding affinity using [3H]pirenzepine and [3H]oxotremorine M as ligands. They were also evaluated fo
- Ishihara,Yukimasa,Miyamoto,Goto
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p. 1177 - 1185
(2007/10/02)
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- Azaspiro compounds and their use
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Azaspiro compounds of the formula STR1 wherein R1 and R2 independently represent hydrogen, a hydrocarbon residue which may have a substituent, or an acyl group which may have a substituent; R3 represents hydrogen or a hydrocarbon residue which may have a substituent; each of X1 and X2 is oxygen or sulfur; Y represents oxygen, sulfur or a group of the formula: --N(R4)--, wherein R4 represents hydrogen or a lower alkyl group; m represents 0 or 1; n represents 0 or 1, and its salt are novel compounds, possess excellent brain function-improving action, and are of use as drugs for the prevention and therapy of senile dementia of Alzheimer type, vascular-type dementia and dementia derived from Alzheimer's disease, Pick's disease, Huntington's disease, Creutzfeldt-Jakob's disease, Parkinson's disease and spinocerebellar degeneration.
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