title: Relationships between structure, antibacterial activity, serum stability, pharmacokinetics and efficacy in 3-(heteroarylthio)cephems. Discovery of RWJ-333441 (MC-04,546).
abstract: SAR studies in a series of related 3-(heteroarylthio)cephems determined that a relatively high chemical reactivity of the beta-lactam ring, modulated by electronic effects of substituents at C-3 and C-7, is necessary to achieve high in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA). Such high reactivity results in lowered hydrolytic stability and concomitantly increases susceptibility to beta-lactam ring opening mediated by serum enzymes. Therefore, optimization of anti-MRSA activity versus stability toward serum-mediated degradation required a fine balance of substituent effects. Serum stability studies (measured as percentage of parent drug degraded after 60 min incubation) revealed up to 80-fold difference in degradation rate in a series of closely related (3-heteroarylthio)cephems. Of the compounds evaluated, RWJ-333441 (MC-04,546) possessed the best balance of serum stability (6% degradation after 60 min incubation) and in vitro activity versus MRSA (S. aureus COL MIC=1 microgram/mL). Accordingly, RWJ-333441 displayed excellent in vivo efficacy versus methicillin-susceptible Staphylococcus aureus (MSSA, ED(50)=0.39 mg/kg in mouse sepsis model with S. aureus Smith) and good pharmacokinetic properties in the rat (Cl(total)=0.39 L/h/kg).
authors.affiliation: Essential Therapeutics, Inc., 850Maude Ave., CA 94043, Mountain View, USA. tglinka@etrx.com
authors.forename: Tomasz
authors.initials: T
authors.lastname: Glinka
authors.forename: Keith
authors.initials: K
authors.lastname: Huie
authors.forename: Aesop
authors.initials: A
authors.lastname: Cho
authors.forename: Maria
authors.initials: M
authors.lastname: Ludwikow
authors.forename: Johanne
authors.initials: J
authors.lastname: Blais
authors.forename: David
authors.initials: D
authors.lastname: Griffith
authors.forename: Scott
authors.initials: S
authors.lastname: Hecker
authors.forename: Michael
authors.initials: M
authors.lastname: Dudley
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002511:Cephalosporins / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D007202:Indicators and Reagents; D007769:Lactams; D008297:Male; D016106:Methicillin Resistance; D051379:Mice; D008826:Microbial Sensitivity Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D007202:Indicators and Reagents; D007769:Lactams; C452865:RWJ-333441