N-aryl cinnamides: A novel class of rigid and highly potent leukotriene B4 receptor antagonists

Greenspan, Paul D.; Main, Alan J.; Bhagwat, Shripad S.; Barsky, L. I.; Doti, Robert A.; Engle, A. R.; Frey, Lisa M.; Zhou, Huanghai; Lipson, Kenneth E.; Chin, M. A.; Jackson, Robert H.; Uziel-Fusi, Susan

doi:10.1016/s0960-894x(97)00134-0

Cited by 7 publications

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“…Olefin reduction (5) and removal of the β-methyl group (4g) both resulted in loss of potency. In addition, compounds 4j and 6, which incorporated elements of an N-arylcinnamide series previously reported by our group (exemplified by compound 2, Chart 1), 13 were prepared but found to be inactive.…”

Section: Resultsmentioning

confidence: 92%

“…Previously, we reported the discovery of potent LTB 4 antagonists, exemplified by the arylamidine CGS 25019C (1) 12 and the phenylcinnamide 2 (Chart 1). 13 As part of our continued effort in this area, we report herein the identification of a novel carboxyphenylcinnamide series of potent, orally active antagonists of the human cellsurface LTB 4 receptor.…”

Section: Introductionmentioning

confidence: 99%

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Carboxy-Substituted Cinnamides: A Novel Series of Potent, Orally Active LTB₄ Receptor Antagonists

et al. 1998

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A series of carboxy-substituted cinnamides were investigated as antagonists of the human cell surface leukotriene B4 (LTB4) receptor. Binding was determined through measurement of [3H]LTB4 displacement from human neutrophils. Receptor antagonism was confirmed through a functional assay, which measures inhibition of Ca2+ release in human neutrophils. Potent antagonists were discovered through optimization of a random screening hit, a p-(alpha-methylbenzyloxy)cinnamide, having low-micromolar activity. Substantial improvement of in vitro potency was realized by the attachment of a carboxylic acid moiety to the cinnamide phenyl ring through a flexible tether, leading to identification of compounds with low-nanomolar potency. Modification of the benzyloxy substituent, either through ortho-substitution on the benzyloxy phenyl group or through replacement of the ether oxygen with a methylene or sulfur atom, produced achiral antagonists of equal or greater potency. The most potent compounds in vitro were assayed for oral activity using the arachidonic acid-induced mouse ear edema model of inflammation. Several compounds in this series were found to significantly inhibit edema formation and myeloperoxidase activity in this model up to 17 h after oral administration. Representatives of this series have been shown to be potent and long-acting orally active inhibitors of the LTB4 receptor.

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Section: Resultsmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Carboxy-Substituted Cinnamides: A Novel Series of Potent, Orally Active LTB₄ Receptor Antagonists

et al. 1998

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ChemInform Abstract: N‐Aryl Cinnamides: A Novel Class of Rigid and Highly Potent Leukotriene B4 Receptor Antagonists.

Greenspan¹,

Main²,

Bhagwat³

et al. 1997

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Several derivatives of the title compound (V) are found to be potent antagonists of the human neutrophil receptor. This series is unique among LTB4 antagonists due to its high degree of rigidity (no yields given). -(GREENSPAN, P. D.; MAIN, A. J.; BHAGWAT, S. S.; BARSKY, L. I.; DOTI, R. A.; ENGLE, A. R.; FREY, L. M.; ZHOU, H.; LIPSON, K. E.; CHIN, M. H.; JACKSON, R. H.; UZIEL-FUSI, S.; Bioorg. Med. Chem. Lett. 7 (1997) 7, 949-954; Arthritis Bone Metab. Res., Novartis Pharm. Corp., Summit, NJ 07901, USA; EN)

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Asthma and Chronic Obstructive Pulmonary Disease

Roth

Green²

2007

Comprehensive Medicinal Chemistry II

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N-aryl cinnamides: A novel class of rigid and highly potent leukotriene B4 receptor antagonists

Cited by 7 publications

References 10 publications

Carboxy-Substituted Cinnamides: A Novel Series of Potent, Orally Active LTB₄ Receptor Antagonists

Carboxy-Substituted Cinnamides: A Novel Series of Potent, Orally Active LTB₄ Receptor Antagonists

ChemInform Abstract: N‐Aryl Cinnamides: A Novel Class of Rigid and Highly Potent Leukotriene B4 Receptor Antagonists.

Asthma and Chronic Obstructive Pulmonary Disease

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N-aryl cinnamides: A novel class of rigid and highly potent leukotriene B4 receptor antagonists

Cited by 7 publications

References 10 publications

Carboxy-Substituted Cinnamides: A Novel Series of Potent, Orally Active LTB4 Receptor Antagonists

Carboxy-Substituted Cinnamides: A Novel Series of Potent, Orally Active LTB4 Receptor Antagonists

ChemInform Abstract: N‐Aryl Cinnamides: A Novel Class of Rigid and Highly Potent Leukotriene B4 Receptor Antagonists.

Asthma and Chronic Obstructive Pulmonary Disease

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Product

Resources

About

Carboxy-Substituted Cinnamides: A Novel Series of Potent, Orally Active LTB₄ Receptor Antagonists

Carboxy-Substituted Cinnamides: A Novel Series of Potent, Orally Active LTB₄ Receptor Antagonists