Substituted tetrahydrofuroyl-1-phenylalanine derivatives as potent and specific VLA-4 antagonists |
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| Authors: | Doherty George A Yang Ginger X Borges Edite Chang Linda L MacCoss Malcolm Tong Sharon Kidambi Usha Egger Linda A McCauley Ermenegilda Van Riper Gail Mumford Richard A Schmidt John A Hagmann William K |
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| Affiliation: | Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. george_doherty@merck.com |
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| Abstract: | A series of substituted tetrahydrofuroyl-1-phenylalanine derivatives was prepared and evaluated as VLA-4 antagonists. Substitution of the alpha carbon of the tetrahydrofuran with aryl groups increased the specificity for VLA-4 versus alpha(4)beta(7) while amide substitution increased the potency of the series without increasing the specificity. Substitution of the beta carbon of the tetrahydrofuran with keto or amino groups slightly improved the specificity for VLA-4 versus alpha(4)beta(7) but with a significant loss in binding affinity for VLA-4. |
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