- Commercialization and late-stage development of a semisynthetic antifungal API: Anidulafungin/D-fructose (eraxis)
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Many years ago anidulafungin 1 was identified as a potentially useful medicine for the treatment of fungal infections. Its chemical and physical properties as a relatively high molecular weight semisynthetic derived from echinocandin B proved to be a significant hurdle to its final presentation as a useful medicine. It has recently been approved as an intravenous treatment for invasive candidaisis, an increasingly common health hazard that is potentially life-threatening. The development and commercialization of this API, which is presented as a molecular mixture of anidulafungin and D-fructose is described. This includes, single crystal X-ray structures of the starting materials, the echinocandin B cyclic-peptide nucleus (ECBN · HCI) and the active ester 1-({[4 - (pentyloxy)-1,1 :4,1-terphenyl-4-yl]carbonyl}oxy)-1H-1,2,3- benzotriazole (TOBt). Details of the structure and properties of starting materials, scale-up chemistry and unusual crystallization phenomena associated with the API formation are discussed.
- Norris, Timothy,VanAlsten, John,Hubbs, Stephen,Ewing, Marcus,Cai, Weiling,Jorgensen, Matthew L.,Bordner, Jon,Jensen, Grace O.
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- Semisynthetic Chemical Modification of the Antifungal Lipopeptide Echinocandin B (ECB): Structure-Activity Studies of the Lipophilic and Geometric Parameters of Polyarylated Acyl Analogs of ECB
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Echinocandin B (ECB) is a lipopeptide composed of a complex cyclic peptide acylated at the N-terminus by linoleic acid.Enzymatic deacylation of ECB provided the peptide "nucleus" as a biologically inactive substrate from which novel ECB analogs were generated by chemical reacylation at the N-terminus.Varying the acyl group revealed that the structure and physical properties of the side chain, particularly its geometry and lipophlicity, played a pivotal role in determining the antifungal potency properties of the analog.Using CLOGP values to describe and compare the lipophlicities of the side chain fragments, it was shown that values of >3.5 were required for expression of antifungal activity.Sercondly, a linearly rigid geometry of the side chain was the most effective shape in enhancing the antifungal potency.Using these parameters as a guide, a variety of novel ECB analogs were synthesized which included arylacyl groups that incorporated biphenyl, terphenyl, tetraphenyl, and arylethynyl groups.Generally the glucan synthase inhibition by these analogs correlated well with in vitro and in vivo activities and was likewise influenced by the structure of the side chain.These structural variations resulted in enhancement of antifungal activity in both in vitro and in vivo assays.Some of these analogs, including LY303336 (14a), were effective by the oral route of administartion.
- Debono, Manuel,Turner, William W.,LaGrandeur, Lisa,Burkhadt, Fred J.,Nissen , Jeffrey S.,et al.
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p. 3271 - 3281
(2007/10/02)
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