ASP9726, A Unique 2nd Generation Echinocandin (2) – Synthesis and In Vitro Activity

Ref ID: 18688

Author:

H. Morikawa, MS – Chemist, A. Okada, PhD – Chemist, M. Tomishima, PhD – Chemist, N. Kayakiri, PhD – Chemist, D. Barrett, PhD – Chemist, S. Akamatsu, MS – Pharmacologist, S. Matsumoto, MS – Pharmacologist, S. Uchida, BS – Pharmacologist, T. Nakai, PhD

Author address:

Astellas Pharma Inc., Tsukuba, Ibaraki, Japan.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: 1st generation echinocandins have insufficient effect against Candida parapsilosis, echinocandin resistant (ER)-Candida, and Aspergillus spp.. 2nd generarion Echinocandins, which posses enhanced antifungal activity against these are needed. Herein, we report a new chemical entity, ASP9726 (ASP) discovered by screening using a novel efficacy marker, the maximum inhibitory effect on Af hypha (Emax). Methods: Extensive synthetic modification of an echinocandin natural product led to discovery of a new type of compound with improved antifungal effect as compared with micafungin (MCFG) and caspofungin (CAS). Emax was assessed by scoring (1-5; 5 is the strongest effect) based on microcolony size and growth of hyphal tip at 4-fold MIC by microscopy. Antifungal effect against Aspergillus fumigatus and Candida spp. was assessed by MIC. MICs were determined according to CLSI M38-A2 in human serum as liquid medium. Results: ASP has a unique class of side chain and bond connection with a modified hexapeptide core nucleus. The side chain was synthesized in 10 steps from commercially available materials. ASP potently inhibited the growth of hyphae of A. fumigatus leading to compact microcolonies as compared with MCFG and CAS, independent of MIC. ASP exhibited broad-spectrum activity against Candida spp. and A. fumigatus and ASP was also effective against C.parapsilosis and ER-Candida. (Table) Conclusions: ASP is a unique new echinocandin derivative derived by chemical modification of a natural product with potent Aspergillus hyphal growth inhibition and significantly improved MIC against C.parapsilosis and ER-Candida. ASP has potential to have significantly improved antifungal activity.

Abstract Number: F-818

Conference Poster: y

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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