The Development of New Carboxylic Acid-Based MMP Inhibitors Derived from a Cyclohexylglycine Scaffold JoshuaS.Tullis, a, * ,y MatthewJ.Laufersweiler, a JohnC.VanRens, a MichaelG.Natchus, a,y Roger G. Bookland, a Neil G. Almstead, a,{ Stanislaw Pikul, a,x Biswanath De, a Lily C. Hsieh, a Michael J. Janusz, a Todd M. Branch, a Sean X. Peng, a Yingkun Y. Jin, a Tomas Hudlicky b and Kofi Oppong b a Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700Mason-Montgomery Rd, Mason, OH 45040, USA b Department of Chemistry, University of Florida, Gainesville, FL 32611, USA Received 18 January 2001; accepted 8 May 2001 Abstract—A series of carboxylic acids was prepared based on cyclohexylglycine scaffolds and tested for potency as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for five enzymes within the MMP family, and a number of inhibitors such as compound 18 display low nanomolar potency for MMP-2 and MMP-13, while selectively sparing MMP-1 and MMP-7. # 2001 Elsevier Science Ltd. All rights reserved. Introduction It has long been postulated that the aberrant over- expression of matrix metalloproteinase enzymes (MMPs) may play a pivotal role in the progression of many pathological disease states where tissue turnover plays a key role. 1 These include osteoarthritis, 2 cancer, 3 congestiveheartfailure, 4 andothers.Thus,considerable interesthasbeendirectedtowardthedirectinhibitionof theMMPs.Themajorityofinhibitorscaffoldsthathave been disclosed contain a hydroxamic acid moiety which contributes key binding interactions to the active site zinc atom. The progression of these compounds in clin- ical trials has been hampered, however, by the emer- gence of musculoskeletal syndrome (MSS). Following a widespread hypothesis that this may be the result of broad spectrum inhibition of the MMP family, a wave of disclosures then followed which described the devel- opment of selective hydroxamate MMPIs which typi- cally spared MMP-1 and MMP-7. 5 Recently, significant interest has been directed toward selective MMPIs that contain a carboxylic acid moiety asazincbindingelementandthiseffortisbenchmarked by BAY-129566 and disclosures by Warner–Lambert 6 and Shionogi (Fig. 1). 7 Both series of compounds con- tain a biaryl moiety that inserts into the P1 0 pocket of MMP enzymes and effectively selects against shallow pocket enzymes such as MMP-1 and -7. We sought to design and target carboxylic acid inhibi- tors that would specifically allow interactions with the S2 pocket of the enzyme and minimize the high protein binding issues reported for BAY-129566. 2 We were encouraged upon the realization of very potent piper- idinyl glycine-based inhibitors, 8 andchosetofollowthis lead with some substituted cyclohexylglycine analogues which we have previously shown to be synthetically accessible. 9 Herein, we communicate the synthesis and 0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved. PII: S0960-894X(01)00371-7 Bioorganic & Medicinal Chemistry Letters 11 (2001) 1975–1979 *Corresponding author. E-mail: jtullis@nutecsciences.com y Current address: NuTec Sciences, 1201 W. Peachtree St., Suite 800, Atlanta, GA 30309, USA. { Current address: PTC Therapeutics, 100 Corporate Ct., South Plain- field, NJ 07080, USA. x Current address: Avalon Pharmaceuticals, 19 Firstfield Rd., Gai- thersburg, MD 20878, USA. Figure 1. Other carboxylic acid based MMP-inhibitors.