L-743,872, a novel antifungal lipopeptide: synthesis and structure-activity relationships of new aza-substituted pneumocandins.

L-743,872, a novel antifungal lipopeptide: synthesis and structure-activity relationships of new aza-substituted pneumocandins.

Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:104 (abstract no. F27). Unique Identifier : AIDSLINE MED/98927649
Bouffard FA; Dropinski JF; Balkovec JM; Black RM; Hammond ML; Nollstadt KH; Dreikorn S; Merck Research Laboratories, Rahway, NJ.

Abstract: Cationic derivatives of pneumocandin B(O) have been shown to be potent inhibitors of beta-1,3-glucan. L-733,560, a bisamine, exhibits potent fungicidal activity in rodent models of systemic candidiasis, aspergillosis, and Pneumocystis carinii pneumonia J. Med. Chem. 37,222-5, 1994). L-733,560 incorporates a hemiaminal aminoethyl ether which was found essential for potent Aspergillus activity. Further modification at the hemiaminal utilizing novel methodology enabling the regioselective introduction of nitrogen nucleophiles under mild conditions will be described. A series of aza-substituted pneumocandins has been prepared and their beta-1,3-glucan IC(50)'s determined in a Candida albicans membrane assay. Minimum inhibitory and minimum fungicidal concentrations vs. a panel of yeast and filamentous clinical isolates determined by broth microdilution will be reported. The exceptional in vitro potency of L-743,872 IC(50)=0.6 nM) combined with its excellent efficacy in vivo and improved pharmacokinetics has led to its selection for clinical development.

Keywords: *Antibiotics, Peptide/PHARMACOLOGY *Antifungal Agents/PHARMACOLOGY
980430
M9841225

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