- Solid-phase synthesis and biological evaluation of piperazine-based novel bacterial topoisomerase inhibitors
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There is an emerging global need for new and more effective antibiotics against multi-resistant bacteria. This situation has led to massive industrial investigations on novel bacterial topoisomerase inhibitors (NBTIs) that target the vital bacterial enzym
- Flagstad, Thomas,Pedersen, Mette T.,Jakobsen, Tim H.,Felding, Jakob,Tolker-Nielsen, Tim,Givskov, Michael,Qvortrup, Katrine,Nielsen, Thomas E.
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supporting information
(2021/12/24)
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- KINETIC RESOLUTION OF CHIRAL AMINES
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The present invention refers to a method for the kinetic resolution of a chiral primary or secondary amine by treating the amine with a chiral, hydroxamic acid derived reagent of the formula (I). These chiral reagents are particularly useful for the kinetic resolution of cyclic amines and may be generated in situ in the presence of an N-heterocyclic carbene, thus allowing for a catalytic reaction.
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Page/Page column 69; 70; 71; 78; 79; 80
(2013/03/26)
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- Expanded substrate scope and catalyst optimization for the catalytic kinetic resolution of N-heterocycles
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The scope, reactivity, and selectivity of the chiral hydroxamic acid-catalyzed kinetic resolution of chiral amines are improved by a new catalyst structure and a more environmentally friendly reaction protocol. In addition to increasing selectivity across all substrates, these conditions make possible the resolution of N-heterocycles containing lactams or other basic functional groups that can inhibit the catalyst.
- Hsieh, Sheng-Ying,Binanzer, Michael,Kreituss, Imants,Bode, Jeffrey W.
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supporting information
p. 8892 - 8894
(2012/11/07)
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- Potent, orally active GPIIb/IIIa antagonists containing a nipecotic acid subunit. Structure-activity studies leading to the discovery of RWJ-53308
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Although intravenously administered antiplatelet fibrinogen receptor (GPIIb/IIIa) antagonists have become established in the acute-care clinical setting for the prevention of thrombosis, orally administered drugs for chronic use are still under development. Herein, we present details from our exploration of structure-activity surrounding the prototype fibrinogen receptor antagonist RWJ-50042 (racemate of 1), which was derived from a unique approach involving the γ-chain of fibrinogen (Hoekstra et al. J. Med. Chem. 1995, 38, 1582). Our analogue studies culminated in the discovery of RWJ-53308 (2), a potent, orally active GPIIb/IIIa antagonist. To progress from RWJ-50042 to a suitable candidate for clinical development, we conducted a series of optimization cycles that employed solid-phase parallel synthesis for the rapid, efficient preparation of nearly 250 analogues, which were assayed for fibrinogen receptor affinity and inhibition of platelet aggregation induced by four different activators. This strategy produced several promising analogues for advanced study, including 3-(3,4- methylenedioxybenzene)-β-amino acid analogue 3 (significant improved in vivo potency) and 3-(3-pyridyl)-β-amino acid 2 (significantly improved potency, oral absorption, and duration of action). In dogs, 2 displayed significant ex vivo antiplatelet activity on oral administration at 1.0 mg/kg, 16% systemic oral bioavailability, minimal metabolic transformation, and an excellent safety profile. Additionally, 2 was found to be efficacious in three in vivo thrombosis models: canine arteriovenous (AV) shunt (0.01-0.1 mg/kg, iv), guinea pig photoactivation-induced injury (0.3-3 mg/kg, iv), and guinea pig ferric chloride-induced injury (0.3-1 mg/kg, iv). On the basis of its noteworthy preclinical data, RWJ-53308 (2) was selected for clinical evaluation.
- Hoekstra, William J.,Maryanoff, Bruce E.,Damiano, Bruce P.,Andrade-Gordon, Patricia,Cohen, Judith H.,Costanzo, Michael J.,Haertlein, Barbara J.,Hecker, Leonard R.,Hulshizer, Becky L.,Kauffman, Jack A.,Keane, Patricia,McComsey, David F.,Mitchell, John A.,Scott, Lorraine,Shah, Rekha D.,Yabut, Stephen C.
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p. 5254 - 5265
(2007/10/03)
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