title: Applying the pro-drug approach to afford highly bioavailable antagonists of P2Y(14).
abstract: Our series of competitive antagonists against the G-protein coupled receptor P2Y(14) were found to be highly shifted in the presence of serum (>99% protein bound). A binding assay using 2% human serum albumin (HSA) was developed to guide further SAR studies and led to the identification of the zwitterion 2, which is substantially less shifted (18-fold) than our previous lead compound 1 (323-fold). However, as the bioavailability of 2 was low, a library of ester pro-drugs was prepared (7a-7j) and assessed in vitro. The most interesting candidates were then profiled in vivo and led to the identification of the pro-drug 7j, which possesses a substantially improved pharmacokinetic profile.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy., Kirkland, Quebec, Canada H9H 3L1. joel_robichaud@merck.com
authors.forename: Joël
authors.initials: J
authors.lastname: Robichaud
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Fournier
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gagné
authors.forename: Jacques Yves
authors.initials: JY
authors.lastname: Gauthier
authors.forename: Martine
authors.initials: M
authors.lastname: Hamel
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Han
authors.forename: Martin
authors.initials: M
authors.lastname: Hénault
authors.forename: Stacia
authors.initials: S
authors.lastname: Kargman
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Levesque
authors.forename: Yaël
authors.initials: Y
authors.lastname: Mamane
authors.forename: Joseph
authors.initials: J
authors.lastname: Mancini
authors.forename: Nicolas
authors.initials: N
authors.lastname: Morin
authors.forename: Erin
authors.initials: E
authors.lastname: Mulrooney
authors.forename: Jin
authors.initials: J
authors.lastname: Wu
authors.forename: W Cameron
authors.initials: WC
authors.lastname: Black
mesh_terms: D001682:Biological Availability; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011485:Protein Binding; D058919:Purinergic P2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D018048:Receptors, Purinergic P2 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C518528:P2Y14 receptor, human; D011355:Prodrugs; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2