N-Tetrahydrofuroyl-(L)-Phenylalanine Derivatives as Potent VLA-4 Antagonists Ginger X. Yang, a, * Linda L. Chang, a Quang Truong, a George A. Doherty, a Plato A. Magriotis, a Stephen E. de Laszlo, a Bing Li, a Malcolm MacCoss, a Usha Kidambi, b Linda A. Egger, b Ermengilda McCauley, b Gail Van Riper, b Richard A. Mumford, b John A. Schmidt b and William K. Hagmann a a Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA b Department of Immunology and Rheumatology Research, Merck Research Laboratories, Rahway, NJ 07065, USA Received 11 December 2001; accepted 8 March 2002 Abstract—Given the proposed involvement of VLA-4 in inflammatory processes, a program to identify orally active VLA-4 antagonists was initiated. Herein, we report the discovery of a N-tetrahydrofuroyl-(l)-phenylalanine derivative (17) and related analogues as potent VLA-4 antagonists with good oral bioavailability. # 2002 Elsevier Science Ltd. All rights reserved. VLA-4 (a 4 b 1 ; ‘very late antigen-4’) is a heterodimeric cell-surface protein expressed at high levels on lympho- cytes. VLA-4 binds to an alternatively spliced segment of fibronectin (CS-1) on extracellular matrix and to vascular cell adhesion molecule-1 (VCAM-1) on endo- thelium. Both of these ligand molecules are expressed in inflamed tissues and actively participate in physiologic and pathologic responses in inflammatory and autoimmune diseases. The binding of VLA-4 to VCAM-1 leads to lymphocyte infiltration to extravascular tissues. Antibodies against VLA-4 have been demonstrated to block lymphocyte infiltration and prevent tissue damage in animal models of inflammatory diseases such as asthma, 1 multiple sclerosis, 2 rheumatoid arthritis, 3 and inflammatory bowel disease. 4 Therefore, an orally active VLA-4 antagonist might be useful in the treatment of these diseases. In a previous communication, 5 we described sulfony- lated prolyl biphenylalanine derivatives 1 as potent VLA-4 antagonists. In this paper, we wish to report our discovery of a series of low molecular weight dipeptides that emerged from the development of 1. Apart from being potent VLA-4 antogonists, such dipeptides show good bioavailability as well. Structure 1 consists of three distinctive regions of pharmacophore depicted as P1, P2, and P3 (Fig. 1). Presently, we wish to report our efforts in the optimization of P1, P2, and P3. That sulfonamides in the P1 region were not essential for potency came as a surprise during a Suzuki-coupling reaction (Fig. 2) of a sulfonylated pyrazolidine. Analysis of the major product of this coupling showed that the sulfonyl group had been eliminated giving rise to the corresponding dehydropyrazolidine 3, which showed interesting VLA-4 activity. 5 The minor product was the desired coupling product 4. To ensure that the observed activity was not due to contamination from the potent sulfonylated pyr- azolidine 4, the dehydropyrazolidine 3 was synthesized via an alternative route (Scheme 1). Starting from the 0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII: S0960-894X(02)00210-X Bioorganic & Medicinal Chemistry Letters 12 (2002) 1497–1500 Figure 1. Binding domains of sulfonylated dipeptides. *Corresponding author. Tel.: +1-732-594-4734; fax: +1-732-594- 9556; e-mail: ginger_yang@merck.com