title: Development of potent non-carbohydrate imidazole-based small molecule selectin inhibitors with antiinflammatory activity.
abstract: A novel series of non-carbohydrate imidazole-based selectin inhibitors has been discovered via high-throughput screening using a P-selectin ELISA-based assay system. The initial lead 1 had an IC(50) of 17 microM in the P-selectin ELISA; this potency was significantly improved via an extensive SAR exploration. One of the current lead compounds (29) has an IC(50) of 300 nM in a P-selectin ELISA; it also has good activity in P- and E-selectin cell adhesion assays and shows efficacy in vivo. These compounds represent a novel series of sLe(X) mimetics with antiinflammatory activity. Their unique profile supports our interest in their further evaluation as drug candidates for the treatment of inflammation. Herein we describe the syntheses, optimization, and SAR of this series of novel potent selectin antagonists.
authors.affiliation: Ontogen Corporation, 2325 Camino Vida Roble, Carlsbad, California, USA. debbie.slee@ontogen.com
authors.forename: D H
authors.initials: DH
authors.lastname: Slee
authors.forename: S J
authors.initials: SJ
authors.lastname: Romano
authors.forename: J
authors.initials: J
authors.lastname: Yu
authors.forename: T N
authors.initials: TN
authors.lastname: Nguyen
authors.forename: J K
authors.initials: JK
authors.lastname: John
authors.forename: N K
authors.initials: NK
authors.lastname: Raheja
authors.forename: F U
authors.initials: FU
authors.lastname: Axe
authors.forename: T K
authors.initials: TK
authors.lastname: Jones
authors.forename: W C
authors.initials: WC
authors.lastname: Ripka
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D016466:CHO Cells; D002240:Carbohydrate Sequence; D002448:Cell Adhesion / Q000187:drug effects; D006224:Cricetinae; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008969:Molecular Sequence Data; D010538:Peritonitis / Q000139:chemically induced / Q000517:prevention & control; D019087:Selectins / Q000187:drug effects*; D013864:Thioglycolates
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007093:Imidazoles; D019087:Selectins; D013864:Thioglycolates