title: Orally active fumagillin analogues: transformations of a reactive warhead in the gastric environment.
abstract: Semisynthetic analogues of fumagillin, 1, inhibit methionine aminopeptidase-2 (MetAP2) and have entered the clinic for the treatment of cancer. An optimized fumagillin analogue, 3 (PPI-2458), was found to be orally active, despite containing a spiroepoxide function that formed a covalent linkage to the target protein. In aqueous acid, 3 underwent ring-opening addition of water and HCl, leading to four products, 4-7, which were characterized in detail. The chlorohydrin, but not the diol, products inhibited MetAP2 under weakly basic conditions, suggesting reversion to epoxide as a step in the mechanism. In agreement, chlorohydrin 6 was shown to revert rapidly to 3 in rat plasma. In an ex vivo assay, rats treated with purified acid degradants demonstrated inhibition of MetAP2 that correlated with the biochemical activity of the compounds. Taken together, the results indicate that degradation of the parent compound was compensated by the formation of active equivalents leading to a pharmacologically useful level of MetAP2 inhibition.
authors.affiliation: Praecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Arico-Muendel
authors.affiliation: Praecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
authors.forename: Heather
authors.initials: H
authors.lastname: Blanchette
authors.affiliation: Praecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Benjamin
authors.affiliation: Praecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Caiazzo
authors.affiliation: Praecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Centrella
authors.affiliation: Praecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: DeLorey
authors.affiliation: Praecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
authors.forename: Elisabeth G
authors.initials: EG
authors.lastname: Doyle
authors.affiliation: Praecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Johnson
authors.affiliation: Praecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Labenski
authors.affiliation: Praecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
authors.forename: Barry A
authors.initials: BA
authors.lastname: Morgan
authors.affiliation: Praecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
authors.forename: Gary
authors.initials: G
authors.lastname: O'Donovan
authors.affiliation: Praecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
authors.forename: Amy A
authors.initials: AA
authors.lastname: Sarjeant
authors.affiliation: Praecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Skinner
authors.affiliation: Praecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Thompson
authors.affiliation: Praecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
authors.forename: Sarah T
authors.initials: ST
authors.lastname: Griffin
authors.affiliation: Praecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
authors.forename: William
authors.initials: W
authors.lastname: Westlin
authors.affiliation: Praecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
authors.forename: Kerry F
authors.initials: KF
authors.lastname: White
keywords: Fumagillin; MetAP2; PPI-2458; angiogenesis inhibitor; irreversible inhibitor