Novel, potent, and orally bioavailable phosphinic acid inhibitors of the hepatitis C virus NS3 protease Michael O. Clarke ⇑ , Xiaowu Chen, Aesop Cho, William E. Delaney IV, Edward Doerffler, Maria Fardis § , Mingzhe Ji, Michael Mertzman   , Rowchanak Pakdaman, Hyun-Jun Pyun, Tanisha Rowe à , Cheng Y. Yang, X. Christopher Sheng, Choung U. Kim Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, USA article info Article history: Received 16 March 2011 Revised 23 April 2011 Accepted 26 April 2011 Available online 3 May 2011 Keywords: HCV NS3 protease Phosphinic acid Carboxylate isostere abstract A potent and novel class of product-like inhibitors of the HCV NS3 protease was discovered by employing a phosphinic acid as a carboxylate isostere. The replicon activity and pharmacokinetic profile of this ser- ies of compounds was optimized by exploring the substitution of the phosphinic acid, as well as conform- ationally constraining these compounds through macrocyclization. The syntheses and preliminary biological evaluation of these phosphinic acids is described. Ó 2011 Elsevier Ltd. All rights reserved. Hepatitis C virus (HCV) has infected an estimated 3% of the world’s population (170 million), making it a serious public health concern. 1 The current standard of care (pegylated interferon-a in combination with ribavirin) is limited in terms of tolerability and efficacy, as only 50% of patients achieve a sustained virological re- sponse. 2 As the currently infected population ages and begins to approach the onset of HCV induced liver cirrhosis and hepatocellu- lar carcinoma, more effective and well tolerated therapies become ever more imperative. Encouragingly, the inhibition of several emerging viral protein targets has shown great promise in clinical trials. Of particular interest is the NS3 protease, a serine protease shown to be essential for viral replication, 3 and more recently, implicated in the ability of HCV to subvert the innate immune re- sponse to its own infection. 4 Clinically, the NS3 protease was first validated by the success achieved with ciluprevir (BI-2061), 5 tela- previr (VX-950), 6 and boceprevir (SCH 503034). 7 In a previous communication others have reported on the de- sign, synthesis and evaluation of a novel series of phosphonate bio- isosteres (Table 1, compounds 2 and 4) of the product-like carboxylic acid inhibitors (Table 1, compounds 1 and 3). 8 While these compounds proved very efficacious in in vitro assays, subsequent pharmacokinetic evaluation showed compound 2 suffered from low bioavailability and intermediate clearance in rats and dogs (F = 0.5%, C L = 0.67 L/h/Kg). It was hypothesized that the poor absorption of compound 2 was partially due to the low pK a of the phosphonic acid. In order to raise the pK a of this phosphorous based bioisostere, a phosphinic acid was proposed as a phosphonate replacement. 9 Orally bioavail- able, small molecule phosphinic acids have been reported, allaying any concerns that phosphinic acids may be intrinsically non- absorbable. 10,11 Molecular modeling (Sybyl, Tripos Inc., St. Louis, MO.) (Fig. 1.) indicated the phosphinic acid 21 would make the same key H-bonds with His57, Ser139, and Gly137, as the phos- phonic acid 2. Molecular modeling, however, also indicated that the phosphinic acid, unlike the phosphonic acid 2, would not form an H-bond with the side chain of Lys136, possibly resulting in a loss in potency. On the whole, though, modeling did indicate that the phosphinic acids would be well tolerated, as the new carbon substi- tution would be pointed away from the protein surface. Further- more, this spatial orientation of the phosphinic acid substitution could allow for its use as a handle to optimize pharmacokinetic profiles. The synthesis of the phosphinic acids began with the CBz pro- tection of amine 5 (Scheme 1), followed by mono-de-ethylation to yield the mono-phosphonic acid 6. 12 The mono-phosphonic acid was then converted into the phosphonochloridate, which could be treated directly with an organolithiate or Grignard reagent, or 0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2011.04.125 ⇑ Corresponding author. Tel.: +1 650 522 6313. E-mail address: Michael.Clarke@gilead.com (M.O. Clarke).   Present address: Lexicon Pharmaceuticals, 350 Carter Rd., Princeton, NJ 08540, USA. à Present address: 1722 Emerald Creek, Florissant, MO 63031, USA. § Present address: Pharmacyclics, 995 E Arques Ave., Sunnyvale, CA 94085, USA. Bioorganic & Medicinal Chemistry Letters 21 (2011) 3568–3572 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl