title: Discovery and development of first in class antifungal caspofungin (CANCIDAS®)--a case study.
abstract: Covering: 1985 to 2001.This paper describes a fifteen year journey from concept to clinical discovery and development of the first in class caspofungin acetate (CANCIDAS®) a parenteral antifungal agent. Caspofungin is a semisynthetic derivative of pneumocandin B0, a naturally occurring, lipophilic cyclic peptide isolated from the fungus, Glarea lozoyensis. While the echinocandins had been previously studied for antifungal activity by several organizations, the class was dropped for a variety of reasons. Merck subsequently initiated a research program leading to the discovery and development of caspofungin. The multitude of challenges that ensued during the discovery and development process and which were successfully resolved by multi-disciplinary teams constitute the content of this article. The article consists of five sections that describe the discovery and development of caspofungin in chronological order: (i) discovery of the natural product pneumocandin B0 from fungal fermentations, (ii) fermentation development to improve the titer of pneumocandin B0 to make it commercially viable, (iii) semisynthetic modification by medicinal chemistry to successfully improve the properties of pneumocandin B0 leading to the discovery of caspofungin, (iv) development of commercial semisynthesis and purification and formulation development to improve stability and (v) clinical development and approval of CANCIDAS® as an antifungal drug which subsequently saved thousands of lives.
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA. sheo.singh.215@gmail.com.
authors.forename: James M
authors.initials: JM
authors.lastname: Balkovec
authors.forename: David L
authors.initials: DL
authors.lastname: Hughes
authors.forename: Prakash S
authors.initials: PS
authors.lastname: Masurekar
authors.forename: Carole A
authors.initials: CA
authors.lastname: Sable
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schwartz
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001203:Ascomycota / Q000737:chemistry*; D000077336:Caspofungin; D055808:Drug Discovery; D054714:Echinocandins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D055666:Lipopeptides; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D010456:Peptides, Cyclic; C079465:pneumocandin B(0); D000077336:Caspofungin