Synthesis and SAR of 4-carboxy-2-azetidinone mechanism-based tryptase inhibitors

Sutton, James; Bolton, Scott A.; Hartl, Karen S.; Huang, Ming‐Hsing; Jacobs, G. A.; Meng, Wei; Ogletree, Martin L.; Pi, Zulan; Schumacher, William A.; Seiler, Steven M.; Slusarchyk, William A.; Treuner, U. D.; Zahler, Robert; Zhao, Guohua; Bisacchi, Gregory S.

doi:10.1016/s0960-894x(02)00688-1

Cited by 64 publications

(37 citation statements)

References 5 publications

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“…Recently, Schumacher et al [18] identified a small-molecule FXIa inhibitor, BMS-262084 (Fig. 1a), from a compound collection of tryptase inhibitors [19], and demonstrated its antithrombotic efficacy in rat models of arterial and venous thrombosis.…”

Section: Introductionmentioning

confidence: 99%

A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits

Wong

Crain

Watson

et al. 2011

J Thromb Thrombolysis

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BMS-262084 is a 4-carboxy-2-azetidinone-containing irreversible inhibitor of FXIa, which is selective over other coagulation proteases. We evaluated the in vitro and in vivo properties of BMS-262084 in rabbits. Studies were conducted in arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT), electrolytic-mediated carotid arterial thrombosis (ECAT) and cuticle bleeding time (BT) models. BMS-262084 was infused IV from 1 h before thrombus induction or cuticle transection to the end of the experiment. In vitro, BMS-262084 prolonged activated partial thromboplastin time (aPTT) with EC(2x) (concentration required to double aPTT) of 10.6 μM in rabbit plasma, and did not prolong prothrombin time (PT), thrombin time (TT) and HepTest. In vivo, BMS-262084 produced dose-dependent antithrombotic effects in rabbits with antithrombotic ED(50) (dose that reduced thrombus weight or increased blood flow by 50% of the control) in AVST, VT and ECAT of 0.4, 0.7 and 1.5 mg/kg/h IV, respectively. BMS-262084 increased ex vivo aPTT dose-dependently without changes in PT and TT. The antithrombotic effect of BMS-262084 was significantly correlated with its ex vivo aPTT, supporting the use of ex vivo aPTT as a pharmacodynamic biomarker. BMS-262084 did not alter ex vivo rabbit platelet aggregation to ADP and collagen. BT (fold-increase) determined at 3 and 10 mg/kg/h of BMS-262084 were 1.17 ± 0.04 and 1.52 ± 0.07*, respectively (*P < 0.05 vs. control). This study demonstrated that BMS-262084 prevented experimental thrombosis at doses with low BT effects in rabbits, and suggests that a small molecule FXIa inhibitor may represent a promising antithrombotic therapy.

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Section: Introductionmentioning

confidence: 99%

A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits

Wong

Crain

Watson

et al. 2011

J Thromb Thrombolysis

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“…Inhibitors of tryptase have potential in the treatment of asthma. [1][2][3] BMS-262084 is a b-lactam peptide that was identified as a potent inhibitor of tryptase 4 with an IC 50 of 4 nM. It is a N1-activated-4-carboxy azetidinone ( Fig.…”

Section: Introductionmentioning

confidence: 99%

“…BMS-262084 demonstrated efficacy after intratracheal dosing in in vivo animal models. 4 The feasibility of oral administration of this compound was investigated in rats. The oral bioavailability of BMS-262084 in rats was very low (4% at 0.5 mg/ kg) due to poor absorption.…”

Section: Introductionmentioning

confidence: 99%

“…11 Because BMS-262084 showed interactions with trypsin, 4 which is present in the gut, the effect of aprotinin on the oral absorption of BMS-262084 was evaluated. Limited studies 13,14 have shown that even hydrophilic compounds that are absorbed predominantly via the paracellular route, may be substrates of P-gp, an efflux transporter that can influence intestinal absorption.…”

Section: Introductionmentioning

confidence: 99%

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Multiple Pathways Are Involved in the Oral Absorption of BMS-262084, a Tryptase Inhibitor, in Rats: Role of Paracellular Transport, Binding to Trypsin, and P-Glycoprotein Efflux

Kamath

Morrison

Harper

et al. 2005

Journal of Pharmaceutical Sciences

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“…c 2005 Wiley Periodicals, Inc. agent clozapine [14], tryptase inhibitors [15,16], antiplatelet agents with antivasodialatory effect [17], sedative and tranquilizers [18], antihelminitic and antifilarial agents [19], antineoplastic agents [7,20,21], as well as antagonist of postsynaptic receptors 5-HT1A [22,23]. The pharmacological potency of such substituted piperazines, as well as the biological activity of 1,2,4-triazole analogues such as fluconazole [24] prompted us to prepare a new series of 1,4-disubtituted piperazines carrying substituted 1,2,4-triazoles and/or methyl group, as potential antitumor candidates.…”

Section: Introductionmentioning

confidence: 99%

New benzylpiperazine derivatives bearing mono‐ and bis‐dialkyl substituted 1,2,4‐triazoles

Al‐Soud¹,

Qalalweh²,

Al-Sa’doni³

et al. 2005

Heteroatom Chemistry

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Cycloaddition of the 1‐aza‐2‐azoniaallenes 3 with p‐cyanobenzyl chlorides afforded, after spontaneous rearrangement, the 1,5‐dialkyl‐3‐[4‐chloromethyl)phenyl]‐1H‐[1,2,4]‐triazoles 6. A series of 1,5‐dialkyl‐1H‐[1,2,4]‐triazol‐3‐yl)benzyl‐piperazines 7 and 8 were prepared from direct condensation of 6 with piperazine and N‐methylpiperazine, respectively. The structures of the newly synthesized products were identified by 2D NMR spectroscopy. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:28–32, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20061

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Synthesis and SAR of 4-carboxy-2-azetidinone mechanism-based tryptase inhibitors

Cited by 64 publications

References 5 publications

A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits

A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits

Multiple Pathways Are Involved in the Oral Absorption of BMS-262084, a Tryptase Inhibitor, in Rats: Role of Paracellular Transport, Binding to Trypsin, and P-Glycoprotein Efflux

New benzylpiperazine derivatives bearing mono‐ and bis‐dialkyl substituted 1,2,4‐triazoles

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