title: 4-[4-[(2-Hydroxybenzoyl)amino]phenyl]butyric acid as a novel oral delivery agent for recombinant human growth hormone.
abstract: A series of N-acetylated, non-alpha, aromatic amino acids was prepared and shown to promote the absorption of recombinant human growth hormone (rhGH) from the gastrointestinal tract. Seventy compounds in this family were tested in vivo in rats. Of the compounds tested, 4-[4-[(2-hydroxybenzoyl)amino]phenyl]butyric acid was identified as a preclinical candidate and was used to demonstrate the oral delivery of rhGH in primates. A significant positive correlation was found between the relative log k' of the delivery agents, as determined by HPLC on an immobilized artificial membrane (IAM) column, and serum rhGH concentrations following oral or colonic dosing in rats. Structure-activity relationships have also been developed on the basis of electronic effects and hydrogen-bonding characteristics of the aromatic amide substituents.
authors.affiliation: Emisphere Technologies, Inc., Hawthorne, New York 10532, USA.
authors.forename: A
authors.initials: A
authors.lastname: Leone-Bay
authors.forename: K K
authors.initials: KK
authors.lastname: Ho
authors.forename: R
authors.initials: R
authors.lastname: Agarwal
authors.forename: R A
authors.initials: RA
authors.lastname: Baughman
authors.forename: K
authors.initials: K
authors.lastname: Chaudhary
authors.forename: F
authors.initials: F
authors.lastname: DeMorin
authors.forename: L
authors.initials: L
authors.lastname: Genoble
authors.forename: C
authors.initials: C
authors.lastname: McInnes
authors.forename: C
authors.initials: C
authors.lastname: Lercara
authors.forename: S
authors.initials: S
authors.lastname: Milstein
authors.forename: D
authors.initials: D
authors.lastname: O'Toole
authors.forename: D
authors.initials: D
authors.lastname: Sarubbi
authors.forename: B
authors.initials: B
authors.lastname: Variano
authors.forename: D R
authors.initials: DR
authors.lastname: Paton
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D015195:Drug Design; D013006:Growth Hormone / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000882:Haplorhini; D006801:Humans; D006860:Hydrogen Bonding; D007408:Intestinal Absorption; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D010654:Phenylbutyrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
chemical_list: C100455:4-(4-((2-hydroxybenzoyl)amino)phenyl)butyric acid; D004337:Drug Carriers; D010654:Phenylbutyrates; D011994:Recombinant Proteins; D013006:Growth Hormone