Waltham, MA, United States
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Green O.M.,Infection Innovative Medicines Unit | McKenzie A.R.,Infection Innovative Medicines Unit | Shapiro A.B.,Infection Innovative Medicines Unit | Otterbein L.,Valeocon Management Consulting | And 6 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

A novel arylsulfonamide-containing series of compounds represented by 1, discovered by highthroughput screening, inhibit the acetyltransferase domain of N-acetylglucosamine-1-phosphate-uridyltransferase/glucosamine-1-phosphate- acetyltransferase (GlmU). X-ray structure determination confirmed that inhibitor binds at the site occupied by acetyl-CoA, indicating that series is competitive with this substrate. This letter documents our early hit-to-lead evaluation of the chemical series and some of the findings that led to improvement in in-vitro potency against Gram-negative and Gram-positive bacterial isozymes, exemplified by compound 40. © 2012 Elsevier Ltd. All rights reserved.


PubMed | Infection Innovative Medicines Unit
Type: Journal Article | Journal: Xenobiotica; the fate of foreign compounds in biological systems | Year: 2015

1.Negamycin exerts its antimicrobial activity by inhibiting bacterial protein synthesis and is efficacious in animal models of infection. In order to optimize negamycin exposure for therapeutic purposes, its pharmacokinetics in pre-clinical species were determined. 2.Negamycin has a dipeptide-like structure with logD7.4 < -1, causing low permeation into Caco-2 cells, low-oral bioavailability in rats of 6% and low-plasma protein binding of 10% in mouse, rat, dog and human plasma. Negamycin degradation rates in microsomes and hepatocytes predicted low-hepatic intrinsic clearance in pre-clinical species, which was confirmed in vivo where clearance varied between 3.4 and 11.5mL/min/kg and virtually all negamycin was cleared unchanged renally. The similar behavior in multiple animal species allowed for the prediction of systemic clearance and volume of distribution in humans using multiple-scaling methods and physiological-based pharmacokinetic modeling and simulation. 3.Only 0.05-0.25% (mol/mol) of administered negamycin was recovered as 2-(1-methylhydrazinyl)acetic acid, a potential reactive metabolite, from rat and dog urine, respectively. 4.In summary, negamycin is a very polar molecule with low-plasma protein binding and low-oral bioavailability that is slowly and exclusively cleared into the urine. Its physicochemical properties make intravenous or intramuscular administration, or a derivative thereof, for therapeutic purposes most likely.

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