Phosphinic Acids: Current Status and Potential for Drug Discovery

REVIEWS Drug Discovery Today Volume 24, Number 3 March 2019 Reviews POST SCREEN Phosphinic acids: current status and potential for drug discovery 1,2,3 3,4 2 2 Moaz M. Abdou , Paul M. O’Neill , Eric Amigues and Magdalini Matziari 1 Egyptian Petroleum Research Institute, Nasr City, PO 11727, Cairo, Egypt 2 Department of Chemistry, Xi’an Jiaotong Liverpool University, Suzhou, Jiangsu 215123, PR China 3 Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK 4 Department of Pharmacology, School of Biomedical Sciences, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, L69 3GE, UK Phosphinic acid derivatives exhibit diverse biological activities and a high degree of structural diversity, rendering them a versatile tool in the development of new medicinal agents. Pronounced recent progress, coupled with previous research findings, highlights the impact of this moiety in medicinal chemistry. Here, we highlight the most important breakthroughs made with phosphinates with a range of pharmacological activities against many diseases, including anti-inflammatory, anti-Alzheimer, antiparasitic, antihepatitis, antiproliferative, anti-influenza, anti-HIV, antimalarial, and antimicrobial agents. We also provide the current status of the corresponding prodrugs, drug-delivery systems, and drug applications of phosphinic acids in the clinical stage Introduction and scope On searching ‘phosphinic acid’ as a keyword in any chemistry The phosphinic acid chemistry story began with the pioneering database; a countless amount of literature references; journal work of August Wilhelm Hofmann in 1855 on methylphosphinic articles; books; and patents appear as proof of its importance acid [1]. The broad biological applications of phosphinic acids are in chemical research; thus; it is impractical to survey the litera- driven by their four combined features: tetrahedral transition state ture of phosphinic acids without narrowing the search to specific resemblance; ability to form electrostatic interactions;, hydrogen perspectives. In this respect; several excellent reviews on numer- bonds; and the capacity to coordinate with diverse metal ions [2]. ous aspects of the synthesis and applications of phosphinic acids These unique features, combined with the ability to incorporate have been published [2–7]. These reviews were devoted to physi- side chains of amino acids provided by these privileged structures, cal; organic; and natural product perspectives; synthetic proce- constitute a firm basis for the discovery of potent and selective dures; including asymmetric synthesis; and their activities as zinc bioactive molecules [3]. Such an approach has been successfully metalloproteinase inhibitors [2–7]. Therefore; a more up-to-date applied to design potent inhibitors of enzymes of medical interest and inclusive survey is required. In continuation of our research [4,5]. Additionally, these classes of compound have shown a in exploring the utilization of phosphinic acids as a structural promising and expanding platform for agrochemicals and indus- motif in medicinal chemistry [7]; here we provide a panoramic trial applications, as well as ligands for transition metal complexes view of the multiple applications of phosphonic acids that ex- [6]. The steady growth in volume and diversity of this class of hibit biological activity alongside appropriate prodrug and drug compounds in many areas of science has stimulated chemists to case studies. We highlight significant advances in phosphinic direct increased efforts to the development of innovative synthetic acid-based molecules in terms of their biological activity and methods for their preparation, with particular attention paid to applications in the treatment of disease. We also present an stereoselective synthesis [7]. overview of the current state of progress that has been made in terms of their prodrug; drug delivery; and drug applications currently in clinical development. Corresponding author: Matziari, M. ([email protected]) 1359-6446/ã 2018 Elsevier Ltd. All rights reserved. 916 www.drugdiscoverytoday.com https://doi.org/10.1016/j.drudis.2018.11.016 Drug Discovery Today Volume 24, Number 3 March 2019 REVIEWS Biological and medicinal significance tively. The basic phosphinopeptide structure discovered by Ravash- Table 1 summarizes the chemical and pharmacological libraries of cino et al. constitutes a starting point for the development of easily the most important phosphinic acid scaffolds (compounds 1–35 accessible and optimized drugs. [8–54]) with a range of pharmacological activities towards several diseases, including anti-inflammatory, anti-Alzheimer, antipara- Anti-HIV agents sitic, antihepatitis, antiproliferative, anti-influenza, anti-HIV, and The phosphinic acid scaffold has been used in anti-HIV-1 aspatic antimalarial compounds. These scaffolds are discussed further acid protease research as a noncleavable transition state analog that below. has provided highly potency analogs (7–12) [13–19]. The c-Phe-Pro inhibitors 7 and 8 exhibit low anti-HIV-1 activity, whereas the Anti-inflammatory agents potency of compounds based on c-Phe-Phe modified structures The most important factor in accelerating inflammatory dis- are more selective than those based on c-Phe-Pro 9 and 10. This 0 eases is the imbalance between proteases and antiproteases [8]. might account for the cyclopentane ring in the P1 -position that POST SCREEN One group of proteases released during inflammation is chy- might not be an optimal mimic of the conformation of a normal mases, which have emerged as potential therapeutic targets that proline residue undergoing pyramidalization at nitrogen during inhibit matrix destruction and tissue remodeling [8]. Therefore, proteolysis. Moreover, elongation of inhibitor 9 to include, sym- 0 Reviews it would be interesting to develop potent and selective chymase metrical to the P positions, a Val-Val sequence at the P2 and P3 inhibitors for therapeutic use. With this objective, Greco et al. positions, provided the potent inhibitor 10. According to the ratio- proposed a series of b-carboxamido-phosphonic acids 1a–e as a nale of the design of these inhibitors, a novel transition-state analog modification of molecule 2 (JNJ-10311795) for obtaining potent mimicking the scissile Phe-Pro has been incorporated into inhibitor inhibitors of human mast cell chymase (Table 1) [8,9]. Favorable 11, which exhibits time-dependent inhibition of HIV protease rat pharmacokinetics data were obtained for 1b (chymase (Ki = 8.2 nM). Interestingly, the insertion of a methyleneamino IC50 = 3.5 nM), and compound 1c (IC50 = 17 nM) was found linker produced a nonhydrolyzable moiety that is likely to be to be orally bioavailable in rats (F = 39%), and orally efficacious zwitterionic near physiological pH. Furthermore, it appears that in a hamster model of inflammation [9], outlining the potential there is a strong pH dependency of HIV-1 protease inhibition for of this class. the phosphinate transition state analogs, with higher Ki values at pH 6.5 compared with pH 4.5, suggesting that the non-ionized phos- Anti-Alzheimer’s agents phinic acid has the highest affinity for the protease. The latest and significant achievements in the therapeutic Over the past 4 years, inhibitors of cyclin-dependent kinases treatment of Alzheimer’s disease (AD) have focused on using (CDKs) have emerged as a potential therapeutic window for HIV BACE1 as a key target for drug development [10]. One of the treatment [20]. Therefore, Orfi et al. [20] synthesized the 12 most potent BACE1 inhibitors is OM00-3 (Ki = 0.3 nM), a sec- phosphinic analog of the sulfonamide LDC000067, one of the ond-generation inhibitor of BACE1 [10]. Manzenrieder et al. [10] most potent CDK9 inhibitors known to date [21]. Phosphinic acid reported the design and synthesis of a phosphinic dipeptide 12 was slightly less potent than LDC000067 as a CDK9 inhibitor isostere of OM00-3, which acts as an inhibitor of human BACE1 (IC50 = 142 nM versus 44 nM for LDC000067) but exhibited high and was developed by replacing the hydroxyethylene isostere of specificity for the CDK9/CycT1 complex. OM00-3 with a phosphinic dipeptide isostere while retaining the amino acid sequence optimized for the hydroxyethylene Anti-hepatitis viral agents isostere. Since the first report of hepatitis C virus (HCV) infection during A series of pseudo phosphinic dipeptide (PDP) inhibitors (3–5) the 1980s, it has been considered a serious public health issue. were screened as inhibitors of human BACE1 using OM00-3 as a Hepacivirin (NS3/4A) protease inhibitors have provided positive reference (IC50 = 6 nM). The phosphinic octapeptide 3 exhibited proof of concept in clinical trials. In recent years, phosphinic acids similar potency towards BACE1 (IC50 = 12 nM), whereas com- have been investigated as carboxylate isosteres and have been pound 4, with an isophthalamide N-terminal mimetic, gave nano- shown to be potent inhibitors of hepacivirin [21]. Clarke et al. molar range potency (IC50 = 360 nM). However, integration of the reported the synthesis and biological evaluation of a series of cyclic PDP isostere with the benzodiazepindione-N-terminal mimetic 5 phosphinic acids (13 and 14) and their acyclic analog (15), which did not improve the inhibitory potency (IC50 = 52 mM). is structurally similar to ciluprevir [21,22]. Development of compounds 13a–f, 14a–c, and 15a–u was achieved by a focused Antiparasitic agents structure–activity relationship (SAR) study that explored

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