Novel Inhibitors of Procollagen C-Terminal Proteinase. Part 1: Diamino Acid Hydroxamates N. G. J. Delaet, a, * ,y L. A. Robinson, a D. M. Wilson, a,{ R. W. Sullivan, a,y E. K. Bradley, a,x S. M. Dankwardt, b R. L. Martin, b H. E. Van Wart b,{ and K. A. M. Walker b a CombiChem Inc., 4570 Executive Drive, San Diego, CA 92121, USA b Roche Bioscience, Inflammatory Diseases Unit, 3401 Hillview Ave, Palo Alto, CA 94304, USA Received 10 January 2003; revised 12 April 2003; accepted 15 April 2003 Abstract—The parallel synthesis of novel inhibitors of procollagen C-terminal proteinase is described. The synthetic strategy allowed for the facile synthesis of a large number of side-chain diversified diamino acid hydroxamates, of which the d-diamino- propionic acid derivatives were shown to be single digit nanomolar PCP inhibitors. # 2003 Elsevier Science Ltd. All rights reserved. The different types of collagens are synthesized as pro- collagen precursor molecules having amino- and car- boxy-terminal peptide extensions, which are specifically removed by two different proteolytic enzymes, pro- collagen N- and C-proteinases. Removal of the solubi- lizing globular domain from the C-terminus of procollagen by procollagen C-terminal proteinase (PCP) results in the production of insoluble fibrillar collagen. The excessive deposition of collagen is associated with a variety of fibrotic diseases, such as interstitial pulmon- ary fibrosis, kidney fibrosis, hepatitis and ARDS and hence inhibition of PCP is an attractive approach for interfering in the progression of fibrosis. 1 Pzrocollagen C-terminal protease is a member of the metzincin enzyme family, as are the matrix metallopro- teases (MMPs). 2 Potent inhibition of MMPs by hydro- xamic acids is extensively documented and several hydroxamates have entered clinical development for cancer and arthritis. 3 In our hands, targeted screening of zinc-ligand containing compounds resulted in the identification of sulfonylated, alkylated d-amino acid hydroxamates as PCP inhibitors. 4 In particular, N-piperonyl 4-methoxybenzene sulfonamide derivatives were shown to confer PCP inhibitory potency. Since these derivatives of b-N-benzoyl Dpr had shown PCP inhibition, we decided to introduce an additional site of diversity, by varying the side-chain length and substitu- tion pattern. The compound libraries reported here and in a subsequent paper were synthesized with the goal of optimizing inhibitory potency vs. the PCP enzyme as well as addressing the physicochemical properties of the initial leads. The synthetic strategy we employed allowed for the rapid, parallel synthesis of hydroxamic acid derivatives of polyfunctionalized amino acids, leading to the facile incorporation of multiple sites of diversity. Because of the successful application of hydroxamic acids as MMP inhibitors, several synthetic approaches, both in solu- tion and on solid support have been reported. 5 In our case, compounds were synthesized using the commer- cially available hydroxylamine chlorotrityl resin, affording the well known advantages of solid-phase synthesis: ease of manipulation of compound libraries, use of the resin as an orthogonal protecting group, removal of non-resin bound impurities or side-products by filtration and the opportunity to drive reactions to completion by use of excess reagents. 6 Hydroxamic acid derivatives of diamino acids (Lys, Orn and Dab) (Scheme 1) were synthesized by coupling of the a-Fmoc, side-chain Dde protected amino acid 7 to deprotected hydroxylamine chlorotrityl resin. Adequate 0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0960-894X(03)00404-9 Bioorganic & Medicinal Chemistry Letters 13 (2003) 2101–2104 *Corresponding author. Tel.:+1-858-964-1417; fax:+1-858-964-1413; e-mail: ndelaet@kemia.com y Current address: Ke´mia Inc., 9390 Towne Centre Drive, Suite 100, San Diego, CA 92121, USA. { Current address: Vertex Pharmaceuticals, 11010 Torreyana Rd., San Diego, CA 92121, USA. x Current address: Sunesis Pharmaceuticals, Inc., 341 Oyster Point Blvd, South San Francisco, CA 94080, USA. k Current address: Metabolix, 3876 Bay Centre Place, Hayward, CA 94545, USA.