Discovery of an Orally Active Series of Isoxazoline Glycoprotein IIb/IIIa Antagonists

Cb, Xue; Wityak, John; Tm, Sielecki; Dj, Pinto; Dg, Batt; Ga, Cain; Sworin, Michael; Al, Rockwell; Jj, Roderick; Wang, S; Mj, Orwat; We, Frietze; Ll, Bostrom; Liu, Jing; Ca, Higley; Fw, Rankin; Ae, Tobin; Emmett, George; Gk, Lalka; Jy, Sze; Sv, Di Meo; Sa, Mousa; Mj, Thoolen; Al, Racanelli; Re, Olson

doi:10.1021/jm960799i

Cited by 67 publications

(69 citation statements)

References 51 publications

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“…We developed selective small-molecule ␣ 2 ␤ 1 inhibitors based on a 2,3-diaminopropionic acid (Dap) backbone (22). The design of these antagonists was based on ␣ 4 ␤ 1 inhibitors incorporating a benzenesulfonyl-prolyl-phenylalanine (ProPhe) scaffold (23)(24)(25) and ␣ IIb ␤ 3 inhibitors containing a Dap moiety (26,27). However, the most potent of the synthesized compounds failed to show sufficient activity in vivo, which prompted us to examine structural modifications to improve the potency.…”

Section: Resultsmentioning

confidence: 99%

“…We then combined the potency-enhancing structural features of compounds 15 and 16, which may have been expected to provide an additive benefit; instead, this combination of substituents led to a dramatic loss in activity (22). Replacing the thioether with a sulfone (24) or an ether (25)(26)(27)) also decreased potency, possibly because of an increase in the polarity of the compounds.…”

Section: Resultsmentioning

confidence: 99%

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Small-molecule inhibitors of integrin α ₂ β ₁ that prevent pathological thrombus formation via an allosteric mechanism

Miller¹,

Basra

Kulp

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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There is a grave need for safer antiplatelet therapeutics to prevent heart attack and stroke. Agents targeting the interaction of platelets with the diseased vessel wall could impact vascular disease with minimal effects on normal hemostasis. We targeted integrin ␣2␤1, a collagen receptor, because its overexpression is associated with pathological clot formation whereas its absence does not cause severe bleeding. Structure-activity studies led to highly potent and selective small-molecule inhibitors. Responses of integrin ␣2␤1 mutants to these compounds are consistent with a computational model of their mode of inhibition and shed light on the activation mechanism of I-domain-containing integrins. A potent compound was proven efficacious in an animal model of arterial thrombosis, which demonstrates in vivo efficacy for inhibition of this platelet receptor. These results suggest that targeting integrin ␣2␤1 could be a potentially safe, effective approach to long-term therapy for cardiovascular disease.I-domain ͉ platelet ͉ thrombosis ͉ integrin ͉ alpha(2) beta(1)

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Small-molecule inhibitors of integrin α ₂ β ₁ that prevent pathological thrombus formation via an allosteric mechanism

Miller¹,

Basra

Kulp

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Synthesis of ISO-1-ISO-1 was synthesized in three steps as described previously (16) and is presented in supplemental Fig. 1.…”

Section: Methodsmentioning

confidence: 99%

ISO-1 Binding to the Tautomerase Active Site of MIF Inhibits Its Pro-inflammatory Activity and Increases Survival in Severe Sepsis

Al‐Abed

Dabideen

Aljabari

et al. 2005

Journal of Biological Chemistry

273

303

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MIF is a proinflammatory cytokine that has been implicated in the pathogenesis of sepsis, arthritis, and other inflammatory diseases. Antibodies against MIF are effective in experimental models of inflammation, and there is interest in strategies to inhibit its deleterious cytokine activities. Here we identify a mechanism of inhibiting MIF pro-inflammatory activities by targeting MIF tautomerase activity. We designed small molecules to inhibit this tautomerase activity; a lead molecule, "ISO-1 ((S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester)," significantly inhibits the cytokine activity in vitro. Moreover, ISO-1 inhibits tumor necrosis factor release from macrophages isolated from LPStreated wild type mice but has no effect on cytokine release from MIFdeficient macrophages. The therapeutic importance of the MIF inhibition by ISO-1 is demonstrated by the significant protection from sepsis, induced by cecal ligation and puncture in a clinically relevant time frame. These results identify ISO-1 as the first small molecule inhibitor of MIF proinflammatory activities with therapeutic implications and indicate the potential of the MIF active site as a novel target for therapeutic interventions in human sepsis.MIF is an important pro-inflammatory cytokine that has been implicated in the pathogenesis of inflammatory disorders (1-6). Administration of neutralizing anti-MIF antibodies has proven therapeutically effective in numerous animal models of systemic inflammation, including Gram-negative, Grampositive, and polymicrobial sepsis, arthritis, and autoimmune diabetes (1-4, 7, 8). Circulating MIF levels are elevated in animals with sepsis and in patients with severe sepsis and septic shock (1). These and other results indicate that inhibiting MIF is a promising approach to develop new anti-inflammatory agents.Three-dimensional x-ray crystallography of MIF shows that the molecule exists as a homotrimer (9 -11). This trimer possesses the ability to catalyze the tautomerization of the non-physiological substrates DL-dopachrome methyl esters (supplemental Fig. 1) into their corresponding indole derivatives (11,12). Crystallographic analysis of MIF complexed with p-hydroxyphenylpyruvic acid, a known MIF substrate (13), has revealed an active site which lies in a hydrophobic cavity formed between two adjacent subunits of the homotrimer (14). Tautomerase activity is an evolutionarily ancient phenomenon, which early life forms presumably utilized for synthesis, but there is no evidence that modern species use this in synthetic pathways. We reasoned that molecules that bind this site could be useful to target MIF function, because the tautomerase activity is expendable. We have designed a molecule to fit into the catalytic site and shown that (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) 2 is a potent inhibitor of MIF tautomerase activity (15). The crystal structure of MIF complexed to ISO-1 reveals that ISO-1 binds to the enzymatic active site. MATERIALS AND MET...

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“…17,38 Further, in contrast to anti-MIF antibody ISO-1 fully penetrates the cells. 38 Therefore, this small chemical inhibitor could potentially exert adverse influences on cell function including pathways involved in provoking cell apoptosis. MIF is not only involved in promotion of inflammation, induction of apoptosis and inhibition of glucocorticoid action, but is also a Figure 6 For caption see page 696.…”

Section: Mif Deficiency Inhibits B-cell Apoptosismentioning

confidence: 99%

Macrophage migration inhibitory factor deficiency protects pancreatic islets from palmitic acid‐induced apoptosis

et al. 2011

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As a result of chronic exposure to high levels of free fatty acids, glucose and inflammatory mediators b-cell apoptosis occurs at the end stage of obesity-associated type 2 diabetes (T2D). One potentially deleterious molecule for b-cell function associated with T2D and obesity in humans is macrophage migration inhibitory factor (MIF). Therefore, the aim of this study was to explore MIF expression in vivo during development of obesity and insulin resistance in high-fat diet (HFD)-fed C57BL/6 mice and whether MIF inhibition could affect b-cell apoptosis and dysfunction induced by palmitic acid (PA) in vitro. Indeed, increase in systemic and locally produced MIF correlated well with the weight gain, triglyceride upregulation, glucose intolerance and insulin resistance, which developed in HFD-fed mice. In in vitro settings PA dose-dependently induced MIF secretion before apoptosis development in islets. Further, mif gene deletion, mRNA silencing or protein inhibition rescued b-cells from PA-induced apoptosis as measured by MTT assay and histone-DNA enzyme linked immuno sorbent assay. Protection from induced apoptosis was mediated by altered activation of caspase pathway and correlated with changes in the level of Bcl-2 family members. Further, MIF inhibition conveyed a significant resistance to PA-induced downregulation of insulin and PDX-1 expression and ATP content. However, b-cell function was not entirely preserved in the absence of MIF judging by low glucose oxidation and depolarized mitochondrial membrane. In conclusion, the observed considerable preservation of b-cells from nutrient-induced apoptosis might implicate MIF as a potential therapeutic target in the later stage of obesity-associated T2D.

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Discovery of an Orally Active Series of Isoxazoline Glycoprotein IIb/IIIa Antagonists

Cited by 67 publications

References 51 publications

Small-molecule inhibitors of integrin α ₂ β ₁ that prevent pathological thrombus formation via an allosteric mechanism

Small-molecule inhibitors of integrin α ₂ β ₁ that prevent pathological thrombus formation via an allosteric mechanism

ISO-1 Binding to the Tautomerase Active Site of MIF Inhibits Its Pro-inflammatory Activity and Increases Survival in Severe Sepsis

Macrophage migration inhibitory factor deficiency protects pancreatic islets from palmitic acid‐induced apoptosis

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Discovery of an Orally Active Series of Isoxazoline Glycoprotein IIb/IIIa Antagonists

Cited by 67 publications

References 51 publications

Small-molecule inhibitors of integrin α 2 β 1 that prevent pathological thrombus formation via an allosteric mechanism

Small-molecule inhibitors of integrin α 2 β 1 that prevent pathological thrombus formation via an allosteric mechanism

ISO-1 Binding to the Tautomerase Active Site of MIF Inhibits Its Pro-inflammatory Activity and Increases Survival in Severe Sepsis

Macrophage migration inhibitory factor deficiency protects pancreatic islets from palmitic acid‐induced apoptosis

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Small-molecule inhibitors of integrin α ₂ β ₁ that prevent pathological thrombus formation via an allosteric mechanism

Small-molecule inhibitors of integrin α ₂ β ₁ that prevent pathological thrombus formation via an allosteric mechanism