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Heterocycle-substituted proline dipeptides as potent VLA-4 antagonists |
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| Authors: | Thomas S Reger Jasmine Zunic Nicholas Stock Bowei Wang Nicholas D Smith Benito Munoz Mitchell D Green Michael F Gardner Joyce P James Weichao Chen Kenneth Alves Qian Si Kelly M Treonze Russell B Lingham Richard A Mumford |
| Institution: | 1. Department of Medicinal Chemistry, Merck Research Laboratories, San Diego, CA 92121, USA;2. Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, San Diego, CA 92121, USA;3. Department of Immunology and Rheumatology Research, Merck Research Laboratories, Rahway, NJ 07065, USA |
| Abstract: | A variety of N-linked tertiary amines and heteroarylamines were examined at the 4-position of sulfonylated proline dipeptides in order to improve VLA-4 receptor off-rates and overcome the issue of CYP3A4 time-dependent inhibition of ester prodrugs. A tight-binding inhibitor 5j with a long off-rate provided sustained receptor occupancy despite poor oral pharmacokinetics. |
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