(9) VRC3324

(10) VRC3375

(11) VRC4307

Perhaps to eliminate the propensity of the hydroxamic acid moiety to hydrolysis, Vicuron and Novartis also explored several series of a-substituted hydroxamic acids as PDF inhibitors [86]. In this study, only hydroxy and fluoro-substituents were tolerated or slightly superior to hydrogen, with thiol, methoxy, amino and larger a-substituents unsuitable. Replacement of the a-methylene with a nitrogen to provide an N-hydroxyurea as the metal-chelating group was also of no advantage, as these analogues lost enzymatic as well as antibacterial activity.

The most advanced PDF inhibitor to emerge thus far from this collaboration is LBM-415 (12) (also called NVP PDF-713 or VIC-104959), an N-formyl-N-hydroxylamine compound still containing a proline residue at P2'. The activity, PK properties, and in vivo efficacy data of (12) were presented at the 14th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) (2004) and the structure of this compound was later presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) (2004). Testing of (12) against a large number of recent clinical isolates (2,625) provided a S. aureus MIC90 — 2 mg/mL (n — 537), a S. pneumoniae MIC90 — 1 mg/mL (n — 504), an enterococci MIC90 — 4 mg/mL (n — 515), and a H. influenzae MIC90 — 8 mg/mL (n — 501) [87]. As expected for a novel antimicrobial agent, (12) is active against drug-resistant bacteria, including MRSA, VRE and multi-drug resistant S. pneumoniae [88, 89]. Compound (12) is a bacte-riostatic agent against S. aureus and bactericidal against some strains of S. pneumoniae [90-93]. This compound demonstrates 62% oral bio-availability in mice, displays non-linear absorption in rats with oral bioavailability of 22-100% at doses ranging from 12 to 436mg/kg [94] and entered Phase I clinical trials in October 2003 (See Clinical Trials section).

Additional P2' proline-containing PDF inhibitors have been reported in the patent literature by Dainippon and Questcor [95, 96]. The Dainippon examples disclosed contain an N-formyl-N-hydroxylamine group and possess good antibacterial activity against S. aureus, S. pneumoniae, Streptococcus pyogenes, Enterococcus faecium and M. catarrhalis [95]. The Questcor patent application describes various proline-containing hydroxamic acid inhibitors [96].

b-Aminohydroxamic acids

In 1975, SAR studies involving actinonin investigated an analogue in which the orientation of the P1'-P2' amide bond was reversed (13), but the compound was found to lack antibacterial activity. Since then, however, descriptions of some b-aminohydroxamic acids and b-amino-N-formyl-N-hydroxylamines as PDF inhibitors have appeared in the patent literature. Patent applications from Senju [97] and De Novo [98] pharmaceuticals cover P1'-P2' amides (14), ureas (15, 16) and sulfonamides (17).


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