Isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives as potent α4β1 integrin antagonists

Duplantier, Allen J.; Beckius, Gretchen E.; Chambers, Robert; Chupak, Louis S.; Jenkinson, Teresa H; Klein, Anita S.; Kraus, Kenneth G.; Kudlacz, Elizabeth M.; McKechney, Michael W; Pettersson, Martin; Whitney, Carrie A; Milici, Anthony J.

doi:10.1016/s0960-894x(01)00511-x

Cited by 12 publications

(6 citation statements)

References 19 publications

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“…These effects have made inhibition of ␣4␤1/VCAM-1 interactions an attractive target for the development of small molecule antagonists. Our studies demonstrate anti-inflammatory activity for several peptidomimetic inhibitors developed through modification of the Leu-Asp-Val sequence, which is a critical region for the binding of ␣4 to the CS-1 region on fibronectin (Duplantier et al, 2001). Compounds resulting from these efforts include CP-664511, which is almost 10 times more potent than BIO1211 in inhibiting Jurkat cell binding to VCAM-1 in the absence of serum and nearly 30 times more potent in its presence.…”

Section: Discussionmentioning

confidence: 85%

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Pulmonary Eosinophilia in a Murine Model of Allergic Inflammation Is Attenuated by Small Molecule α4β1 Antagonists

Kudlacz

Whitney²,

Andresen³

et al. 2002

J Pharmacol Exp Ther

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Inhibition of ␣4␤1/vascular cell adhesion molecule-1 (VCAM-1) interactions have therapeutic potential in treating allergic airway disease because of the importance of these adhesion molecules in the trafficking of eosinophils, lymphocytes, and monocytes. We examined several small molecule inhibitors of ␣4␤1/VCAM-1 interactions with in vitro potencies (IC 50 values) ranging from 0.52 nM (CP-664511; 3-The same compounds were evaluated in vivo using a murine model of ovalbumin-induced pulmonary eosinophilia. In this model, systemic administration of antibodies against ␣4 reduced bronchoalveolar lavage (BAL) eosinophilia ϳ60%. Small molecule ␣4␤1 antagonists were administered by intratracheal instillation and demonstrated dose-dependent inhibition of BAL eosinophil numbers and achieved a maximum inhibition of ϳ60%. In general, the rank order of potency for these compounds in vitro was consistent with that observed in vivo, which confirms that their efficacy is likely via blockade of ␣4␤1/VCAM-1 interactions. The most potent compound, CP-664511, also inhibited BAL eosinophilia following s.c. administration (1-10 mg/kg, s.c.). These data support the utility of small molecule ␣4␤1 antagonists in the treatment of relevant diseases, such as asthma.

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Section: Discussionmentioning

confidence: 85%

“…Unless otherwise specified, compounds were obtained from Sigma-Aldrich (St. Louis, MO). All ␣4␤1 antagonists were synthesized at Pfizer Central Research as described elsewhere (Duplantier et al, 2001; Fig. 1).…”

Section: Methodsmentioning

confidence: 99%

Pulmonary Eosinophilia in a Murine Model of Allergic Inflammation Is Attenuated by Small Molecule α4β1 Antagonists

Kudlacz

Whitney²,

Andresen³

et al. 2002

J Pharmacol Exp Ther

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“…To circumvent the shortcomings of VLA4-targeting compounds hitherto tested as mobilizing agents, we selected a series of VLA4 antagonists that had been developed based on the structure of the well-known VLA4 inhibitors BIO5192 (28) and firategrast (24,25). These compounds (CWHM-822, 823, 824, 825, and 842; Figure 1C) were synthesized as previously described (29)(30)(31)(32)(33)(34). Properties of the inhibitors were assessed using a colorimetric, cell-free, solid-phase receptor binding assay (SPRA; Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/JCI124738DS1) as well as a flow cytometry-based soluble VCAM1 binding assay ( Figure 1D).…”

Section: Resultsmentioning

confidence: 99%

Targeting VLA4 integrin and CXCR2 mobilizes serially repopulating hematopoietic stem cells

Karpova¹,

Rettig²,

Ritchey³

et al. 2019

Journal of Clinical Investigation

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he is an Advisory Board Member for Cellworks Group, RiverVest Venture Partners, and Arch Oncology. DMM is an employee of and owns equity in Magenta Therapeutics Inc. PGR has stock in Pfizer Inc. PGR and DWG are cofounders of, consultants for, and own equity in Indalo Therapeutics, a company pursuing clinical development of RGD-binding integrin antagonists, but not of antagonists of a α4β1 (VLA4). MPR serves as a consultant for RiverVest Venture Partners, and has received research funding from Amphivena Therapeutics, Novimmmune, and Cantex. MJM receives research funding from Ultragenyx Pharmaceutical Inc. and is the founder and owner of Meyers MedChem Consulting LLC. RFH is currently an employee of Confluence Discovery Technologies. LE has received research funding from MaxCyte Inc. HBB is a coinventor of patent PCT/EP2015/066083 from which he receives royalties and licensing fees; he has received honoraria from Miltenyi,

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“…70 In an effort to improve oral bioavailability of the LDV trimer, the aspartic acid moiety was incorporated into a heterocycle and the valine was removed, thus reducing the number of metabolically labile amide bonds. 71 Compounds were screened for VLA-4 antagonist activity in a Jurkat cell ELISA assay and a human eosinophil cell-binding scintillation proximity assay (SPA). Isoxazole, isoxazoline, oxazole, and thiazole were equally potent (15a-15d).…”

Section: B Linear Peptides-ldv Mimeticsmentioning

confidence: 99%

VLA‐4 antagonists: Potent inhibitors of lymphocyte migration

Yang

Hagmann

2003

Medicinal Research Reviews

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Circulating lymphocytes normally migrate through extravascular spaces in relatively low numbers as important members of the immunosurveillance process. That is until signals are received by endothelial cells that there is an underlying infection or inflammatory condition. These vascular surface cells in turn overexpress and present ligands to circulating lymphocyte adhesion molecules. Upon encountering this higher density of ligands, lymphocytes, which had been leisurely rolling along the vascular surface, now become more firmly attached, change shape, and migrate through tight junctions to the sites of infection or inflammation. If the initiating events are not resolved and the condition becomes chronic, there can be a sustained extravasation of lymphocytes that can exacerbate the inflammatory condition, which in turn will continue to recruit more inflammatory cells resulting in unwanted tissue destruction. It is for the attenuation of this cycle of sustained inflammatory cell recruitment that very late activating antigen-4 (VLA-4) antagonists are being developed. Most lymphocytes, except neutrophils, express VLA-4 on their surface and they interact with endothelial vascular cell adhesion molecule-1 (VCAM-1). It is this interaction that VLA-4 antagonists are intended to disrupt, thus, putting an end to the cycle of chronic inflammation, which is the hallmark of many diseases. This review will provide an update of VLA-4 antagonists that have appeared since early 2001 and will discuss some of the issues, both positive and negative, that may be encountered in their development.

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Isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives as potent α4β1 integrin antagonists

Cited by 12 publications

References 19 publications

Pulmonary Eosinophilia in a Murine Model of Allergic Inflammation Is Attenuated by Small Molecule α4β1 Antagonists

Pulmonary Eosinophilia in a Murine Model of Allergic Inflammation Is Attenuated by Small Molecule α4β1 Antagonists

Targeting VLA4 integrin and CXCR2 mobilizes serially repopulating hematopoietic stem cells

VLA‐4 antagonists: Potent inhibitors of lymphocyte migration

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