title: Discovery of Orally Available Prodrugs of the Glutamate Carboxypeptidase II (GCPII) Inhibitor 2-Phosphonomethylpentanedioic Acid (2-PMPA).
abstract: 2-Phosphonomethylpentanedioic acid (1, 2-PMPA) is a potent inhibitor of glutamate carboxypeptidase II which has demonstrated robust neuroprotective efficacy in many neurological disease models. However, 1 is highly polar containing a phosphonate and two carboxylates, severely limiting its oral bioavailability. We strategized to mask the polar groups via a prodrug approach, increasing the likelihood of passive oral absorption. Our initial strategy was to cover the phosphonate with hydrophobic moieties such as pivaloyloxymethyl (POM) and isopropyloxycarbonyloxymethyl (POC) while keeping the α- and γ-carboxylates unsubstituted. This attempt was unsuccessful due to the chemical instability of the bis-POC/POM derivatives. Addition of α,γ-diesters and α-monoesters enhanced chemical stability and provided excellent oral exposure in mice, but these mixed esters were too stable in vivo, resulting in minimal release of 1. By introducing POC groups on both the phosphonate and α-carboxylate, we synthesized Tris-POC-2-PMPA (21b), which afforded excellent release of 1 following oral administration in both mice and dog.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., 166 10 Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Majer
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., 166 10 Prague, Czech Republic.
authors.forename: Andrej
authors.initials: A
authors.lastname: Jančařík
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., 166 10 Prague, Czech Republic.
authors.forename: Marcela
authors.initials: M
authors.lastname: Krečmerová
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., 166 10 Prague, Czech Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Tichý
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., 166 10 Prague, Czech Republic.
authors.forename: Lukáš
authors.initials: L
authors.lastname: Tenora
authors.affiliation: Johns Hopkins Drug Discovery, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Wozniak
authors.affiliation: Johns Hopkins Drug Discovery, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Johns Hopkins Drug Discovery, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors.forename: Elie
authors.initials: E
authors.lastname: Pommier
authors.affiliation: Department of Chemistry, McDaniel College , Westminster, Maryland 21157, United States.
authors.forename: Dana
authors.initials: D
authors.lastname: Ferraris
authors.affiliation: Johns Hopkins Drug Discovery, Johns Hopkins University , Baltimore, Maryland 21205, United States.|Johns Hopkins Department of Neurology, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors.forename: Rana
authors.initials: R
authors.lastname: Rais
authors.affiliation: Johns Hopkins Drug Discovery, Johns Hopkins University , Baltimore, Maryland 21205, United States.|Johns Hopkins Department of Neurology, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000954:Antigens, Surface; D001682:Biological Availability; D004285:Dogs; D055808:Drug Discovery; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000954:Antigens, Surface; D018696:Neuroprotective Agents; D011355:Prodrugs; D011480:Protease Inhibitors; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II