Kaul Malvika, Mark Lilly, Zhang Yongzheng, Parhi Ajit K, Lyu Yi Lisa, Pawlak Joan, Saravolatz Stephanie, Saravolatz Louis D, Weinstein Melvin P, LaVoie Edmond J, Pilch Daniel S
Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
TAXIS Pharmaceuticals, Inc., North Brunswick, New Jersey, USA Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey, USA.
Antimicrob Agents Chemother. 2015 Aug;59(8):4845-55. doi: 10.1128/AAC.00708-15. Epub 2015 Jun 1.
The clinical development of FtsZ-targeting benzamide compounds like PC190723 has been limited by poor drug-like and pharmacokinetic properties. Development of prodrugs of PC190723 (e.g., TXY541) resulted in enhanced pharmaceutical properties, which, in turn, led to improved intravenous efficacy as well as the first demonstration of oral efficacy in vivo against both methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). Despite being efficacious in vivo, TXY541 still suffered from suboptimal pharmacokinetics and the requirement of high efficacious doses. We describe here the design of a new prodrug (TXA709) in which the Cl group on the pyridyl ring has been replaced with a CF3 functionality that is resistant to metabolic attack. As a result of this enhanced metabolic stability, the product of the TXA709 prodrug (TXA707) is associated with improved pharmacokinetic properties (a 6.5-fold-longer half-life and a 3-fold-greater oral bioavailability) and superior in vivo antistaphylococcal efficacy relative to PC190723. We validate FtsZ as the antibacterial target of TXA707 and demonstrate that the compound retains potent bactericidal activity against S. aureus strains resistant to the current standard-of-care drugs vancomycin, daptomycin, and linezolid. These collective properties, coupled with minimal observed toxicity to mammalian cells, establish the prodrug TXA709 as an antistaphylococcal agent worthy of clinical development.
像PC190723这样的靶向FtsZ的苯甲酰胺类化合物的临床开发受到类药性质和药代动力学性质不佳的限制。PC190723（如TXY541）前药的开发导致药物性质增强，进而提高了静脉给药疗效，并首次证明了其在体内对甲氧西林敏感金黄色葡萄球菌（MSSA）和耐甲氧西林金黄色葡萄球菌（MRSA）的口服疗效。尽管TXY541在体内有效，但仍存在药代动力学不理想以及需要高有效剂量的问题。我们在此描述了一种新前药（TXA709）的设计，其中吡啶环上的Cl基团已被抗代谢攻击的CF3官能团取代。由于这种增强的代谢稳定性，TXA709前药的产物（TXA707）具有改善的药代动力学性质（半衰期延长6.5倍，口服生物利用度提高3倍），并且相对于PC190723具有更优异的体内抗葡萄球菌疗效。我们验证了FtsZ是TXA707的抗菌靶点，并证明该化合物对耐当前标准治疗药物万古霉素、达托霉素和利奈唑胺的金黄色葡萄球菌菌株仍具有强大的杀菌活性。这些综合性质，再加上对哺乳动物细胞观察到的最小毒性，确立了前药TXA709作为一种值得临床开发的抗葡萄球菌药物。
