Solid-Phase Synthesis of an Arylsulfone Hydroxamate Library Joseph M. Salvino,* Rose Mathew, Terence Kiesow, Ramesh Narensingh, Helen J. Mason, Amy Dodd, Robert Groneberg, Christopher J. Burns, Gerald McGeehan, Jane Kline, Edward Orton, Sheng-Yuh Tang, Mathew Morrisette and Richard Labaudininiere Rhone Poulenc Rorer, Lead Discovery and Medicinal Chemistry Departments, 500 Arcola Road, Collegeville, PA 19426, USA Received 12 November 1999; accepted 8 May 2000 AbstractÐSynthesis of an arylsulfone hydroxamate lead optimization library is presented. Biological activity of representative examples is given to demonstrate the value of this approach for lead optimization. # 2000 Elsevier Science Ltd. All rights reserved. Introduction The solid-phase synthesis and biological activity of an arylsulfone hydroxamate library is described. The goal of this work was to develop a solid-phase route to the arylsulfone hydroxamate chemical series 1 to facilitate optimization of this lead series. The preliminary SAR on a b-arylsulfone hydroxamate scaold capable of inhibiting either MMPs or PDE4 has recently been disclosed. These targets are of considerable interest as anti-in¯ammatory agents. 1,2 As part of this study a general synthetic route for chemical libraries of carboxylic and hydroxamic acids was designed and carried to fruition. In this report we wish to disclose this solid-phase synthesis and the resulting SAR required for potent, selective MMP or PDE4 inhibitors. Chemistry A ®ve-step solution route to the arylsulfone inhibitors (compound 8; Scheme 2), had been developed prior to starting this project. 1 However, this route involved chromatographic puri®cation after each synthetic step. A robust solid-phase route would facilitate puri®cation and thus make the entire process more ecient. A solid- phase synthesis of the carboxylic acid sulfone was developed (Scheme 1). 3 This synthesis was ¯exible enough to allow for the isolation and screening of all the carboxylic acid intermediates. A resin bound hydroxyl- amine was employed to transform the carboxylic acid into the hydroxamic acid 4 (Scheme 2). Typically, the reaction products displayed >80% purity as determined by 0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved. PII: S0960-894X(00)00285-7 Bioorganic & Medicinal Chemistry Letters 10 (2000) 1637±1640 Scheme 1. Reagents. (a) Phosphonoacetic acid (3 equiv), 2,6-dichlorobenzoylchloride (3.2 equiv), anhydrous pyridine (6.4 equiv), DMF, 25  C, 8 h; (b) Lithium bis(trimethylsilyl)amide (5 equiv), THF, 0  C to 25  C, 60 min then ®lter under argon, add R 1 CHO (4 equiv), 60% cyclohexane in THF 25  C 24± 48 h; (c) HSR 2 (5 equiv), THF, nBuLi (0.1 equiv), 25  C, 12 h; (d) mCPBA (5 equiv), dioxane, 25  C, 12h; (e) 30% TFA in CH 2 Cl 2 (excess), 25  C, 1 h. *Corresponding author. Adolor Corp., 371 Phoenixville Pike, Malvern, PA 19355, USA. Tel.: +1-610-287-6953; fax: +1-610-889-2203; e-mail: Jsalvino@aol.com