Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors. 6. Structure−Activity Studies of Orally Bioavailable, 2-Pyridone-Containing Peptidomimetics

Abstract

The structure-based design, chemical synthesis, and biological evaluation of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of a peptidomimetic binding determinant and a Michael acceptor moiety, which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The 2-pyridone-containing inhibitors typically display improved 3CP inhibition properties relative to related peptide-derived molecules along with more favorable antiviral properties. The cocrystal structure of one pyridone-derived 3CP inhibitor complexed with HRV-2 3CP is also described along with certain ab initio conformation analyses. Optimization of the 2-pyridone-containing compounds is shown to provide several highly active 3CP inhibitors (k(obs)/[I] > 500,00 M(-1) s(-1)) that function as potent antirhinoviral agents (EC(50) = <0.05 microM) against multiple virus serotypes in cell culture. One 2-pyridone-containing 3CP inhibitor is shown to be bioavailable in the dog after oral dosing (F = 48%).

Structural Determinant of Human La Protein Critical for Internal Initiation of Translation of Hepatitis C Virus RNA

“…Many of the problems associated with the use of therapeutic peptides are gradually being solved. In fact, a number of peptidomimetic structures are currently being tried as antiviral agents (8,14). One of the best approaches in the design of effective peptidomimetic structure is to replace naturally occurring amino acids with synthetic amino acids that stabilize the interacting conformation guided by the structure of the peptide.…”

Synthesis and self-assembly of novel fluorous cationic amphiphiles with a 3,4-dihydro-2(1H)-pyridone spacer

“…Laser 633 nm and software of Malvern Instruments Ltd. 3.2. 5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-Heptadecafluorododecyl 3-oxobutanoate (1) 5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-Heptadecafluorododecanol 6.45 g (0.0131 mol) and 2,2,6-trimethyl-4H-1,3-dioxin-4-one 1.86 g (0.0131 mol) in 50 mL p-xylene were heated in an oil bath and stirred at 160 8C for 2 h. The solvent was removed on a rotary evaporator to give 6.89 g of a light yellow oil. The oil was purified by a silica gel column using EtOAc/hexane as eluent 800 mL 5% and 500 mL 10% in EtOAc, the fractions were monitored on silica TLC plates with phosphomolybdic acid developer.…”

“…1 3.3. 5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-Heptadecafluorododecyl 2-methyl-6-oxo-4-phenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (2) An RB flask fitted with a water cooled condenser and a CaCl 2 guard tube was charged with Meldrum's acid 1.03 g (7.2 mmol), benzaldehyde 0.76 g (7.2 mmol), the above perfluoroalkyl acetoacetate (1) 4.13 g (7.2 mmol), ammonium acetate 0.83 g (10 mmol), and 12 mL glacial acetic acid. The reaction mixture was stirred magnetically and heated to reflux in an oil bath for 6.5 h, after which the heating was stopped and left stirring overnight.…”

“…Milrinone, Amrinone [6] and their analogs are cardiotonic agents for the treatment of heart failure. They have also been reported to possess antitumor [7,8], antibacterial [9] and other biological activities [10][11][12].…”

Hydrogen bonding interaction of CpCo(Dithiolene) complex with monocyclic 2-pyridonyl substituent and unexpected formation of dithiolene-fused tricyclic pyridone derivative

“…Nishihara et al On the other hand, 2-pyridone derivatives have been attracted due to their promising features as an important core structure for the development of biologically active molecules [12]. Pharmaceuticals with the 2-pyridone structure have been investigated for antitumor [13], antifungal [14], antibacterial [15], antiviral [16], and antithrombotic agents [17]. In general, 2-pyridone derivatives could be one of strong hydrogen bonding motifs by the NHÁ Á ÁO interaction.…”