title: Structure-based organic synthesis of unnatural aeruginosin hybrids as potent inhibitors of thrombin.
abstract: Based on X-ray crystallographic data of complexes of chlorodysinosin A with the enzyme thrombin, a series of analogs were synthesized varying the nature of the P(1), P(2), and P(3) pharmacophoric sites and the central octahydroindole carboxyamide core. In general, introduction of a hydrophobic substituent on the d-leucine amide residue dramatically improved the inhibition of the enzyme. This is rationalized based on a better fit of the P(3) subunit in the hydrophobic S(3) enzyme site. Single digit nanomolar inhibition expressed as IC(50) was observed for several analogs.
authors.affiliation: Department of Chemistry, Université de Montréal, PO Box 6128, Station, Centre-Ville, Montréal, QC, Canada H3C 3J7. Stephen.hanessian@umontreal.ca
authors.forename: Stephen
authors.initials: S
authors.lastname: Hanessian
authors.forename: Karolina
authors.initials: K
authors.lastname: Ersmark
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Wang
authors.forename: Juan R
authors.initials: JR
authors.lastname: Del Valle
authors.forename: Niklas
authors.initials: N
authors.lastname: Blomberg
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Xue
authors.forename: Ola
authors.initials: O
authors.lastname: Fjellström
mesh_terms: D000577:Amides / Q000737:chemistry; D000991:Antithrombins / Q000138:chemical synthesis / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007930:Leucine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D008956:Models, Chemical; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D000577:Amides; D000991:Antithrombins; D007211:Indoles; D009842:Oligopeptides; D013917:Thrombin; D007930:Leucine