title: SAR studies of anti-MRSA non-zwitterionic 3-heteroarylthiocephems.
abstract: SAR studies in a series of 3-heteroarylthio substituted cephalosporins established that high activity against methicillin-resistant Staphylococcus aureus (MRSA) can be achieved with various heteroaryl substituents. Early results showed that highly lipophilic 3-heteroarylthio substituents, which were necessary for anti-MRSA activity, caused high affinity of such cephems toward serum proteins. Our earlier published efforts described discovery of zwitterionic cephems MC-02,331 and RWJ-54428 (MC-02,479), where serum binding was reduced by employing basic, positively charged functionalities attached to the 3-heteroarylthio substituent. In order to avoid low solubility problems associated with most such zwitterionic cephalosporins a wide variety of non-basic heteroaryl substituents was tested (non-zwitterionic cephems are more easily formulated as water soluble sodium salts for intravenous administration). Considerable reduction in serum binding was obtained in some analogs while maintaining high anti-MRSA potency.
authors.affiliation: Microcide Pharmaceuticals, Mountain View, CA, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: Glinka
authors.forename: A
authors.initials: A
authors.lastname: Cho
authors.forename: Z J
authors.initials: ZJ
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Ludwikow
authors.forename: D
authors.initials: D
authors.lastname: Griffith
authors.forename: K
authors.initials: K
authors.lastname: Huie
authors.forename: S J
authors.initials: SJ
authors.lastname: Hecker
authors.forename: M N
authors.initials: MN
authors.lastname: Dudley
authors.forename: V J
authors.initials: VJ
authors.lastname: Lee
authors.forename: S
authors.initials: S
authors.lastname: Chamberland
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002511:Cephalosporins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D016106:Methicillin Resistance; D051379:Mice; D008826:Microbial Sensitivity Tests / Q000379:methods; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D001798:Blood Proteins; D002511:Cephalosporins