PF-5081090

PF-5081090 (LpxC-4) is a potent LpxC inhibitor, is a rapidly bactericidal with broad-spectrum activity. PF-5081090 serves as a regulator of lipid A biosynthesis in Gram-negative pathogens^[1][2]. In Vitro: PF-5081090 shows strong potency against a broad spectrum of Gram-negative pathogens with IC₅₀s of 1.1 nM (P. aeruginosa), 0.069 nM (K. pneumonia) and MIC₉₀s of 1 μg/mL (P. aeruginosa, K. pneumoniae), 0.25 μg/mL (E. coli), 0.5 μg/mL (Enterobacter spp), 2 μg/mL (S. maltophilia)^[1].
PF-5081090 (0.25 μg/mL; 0-50 h) demonstrates sustained bactericidal activities against P. aeruginosa UC12120 (A), PA-1955 (B), and K. pneumoniae KP-1487^[1].
PF-5081090 (32 mg/L) increases antibiotic susceptibility in Acinetobacter baumannii with rifampicin, vancomycin, azithromycin, imipenem and amikacin^[2].
PF-5081090 (32 mg/L) inhibits lipid A biosynthesis, and significantly increases cell permeability in A. baumannii^[2]. In Vivo: PF-5081090 (8.75, 75, 300 mg/kg; s.c.; single dose) exhibits a exposure increasing in linear manner across the dose range in mice, with area under the concentration-time curve (AUC) and maximum concentration of drug in serum (C_max) increasing with a proportional increase in dose^[1].
PF-5081090 shows potent efficacies against sentinel strains of P. aeruginosa and K. pneumonia in CD-1 mice, with effective dose (ED₅₀) ranging from 7.4-55.9 mg/kg (against acute septicemia model), <25 mg/kg (against pneumonia model), and 16.8 mg/kg (against neutropenic thigh model) in mice infected with P. aeruginosa PA-1950^[1].
Pharmacokinetics of PF-5081090 in CD-1 mice^a[1]

Dose (mg/kg)	Cmax (mg/L)	Tmax (h)	AUC (h mg/L)	Free AUC (h mg/L)	T1/2 (h)	CL (L/h/kg)	Vss (L/kg)
18.75	5.02	0.25	5.09	1.58	0.6	3.79	2.20
75	15.50	0.33	17.60	5.46	0.69	4.32	3.30
300	75.40	0.33	76.30	23.70	0.68	3.92	2.53

^a Following single subcutaneous doses.