Hydrophobic vancomycin derivatives with improved ADME properties: discovery of telavancin (TD-6424).
Novel derivatives of N-decylaminoethylvancomycin (2), containing appended hydrophilic groups were synthesized and their antibacterial activity and ADME properties were evaluated. The compounds were prepared by reacting amines with the C-terminus (C-) of 2 using PyBOP mediated amide formation, or with the resorcinol-like (R-) position of 2 using a Mannich aminomethylation reaction. These analogs retained the antibacterial activity of 2 against methicillin-resistant staphylococci and vancomycin-resistant enterococci. Compounds with a negatively charged auxiliary group also exhibited improved ADME properties relative to 2. In particular, R-phosphonomethylaminomethyl derivative 21 displayed good in vitro antibacterial activity, high urinary recovery and low distribution to liver and kidney tissues. Based on these results, 21 was advanced into development as TD-6424, and is currently in human clinical trials. The generic name telavancin has recently been approved for compound 21.
Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA. mleadbetter@theravance.com
Michael R
MR
Leadbetter
Stacy M
SM
Adams
Bettina
B
Bazzini
Paul R
PR
Fatheree
Dane E
DE
Karr
Kevin M
KM
Krause
Bernice M T
BM
Lam
Martin S
MS
Linsell
Matthew B
MB
Nodwell
John L
JL
Pace
Kelly
K
Quast
Jeng-Pyng
JP
Shaw
Elizabeth
E
Soriano
Sean G
SG
Trapp
Jenny D
JD
Villena
Terry X
TX
Wu
Burton G
BG
Christensen
J Kevin
JK
Judice
D000617:Aminoglycosides / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006094:Gram-Positive Bacteria / Q000187:drug effects; D007202:Indicators and Reagents; D007275:Injections, Intravenous; D000077427:Lipoglycopeptides; D008826:Microbial Sensitivity Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet; D017334:Teicoplanin / Q000494:pharmacology; D014018:Tissue Distribution; D014640:Vancomycin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D007202:Indicators and Reagents; D000077427:Lipoglycopeptides; D017334:Teicoplanin; D014640:Vancomycin; C487637:telavancin