Hydrophobic Vancomycin Derivatives with Improved ADME Properties Discovery of Telavancin (TD-6424)

MICHAEL R. LEADBETTER; STACY M. ADAMS; BETTINA BAZZINI; PAUL R. FATHEREE; DANE E. KARR; KEVIN M. KRAUSE; BERNICE M. T. LAM; MARTIN S. LINSELL; MATTHEW B. NODWELL; JOHN L. PACE; KELLY QUAST; JENG-PYNG SHAW; ELIZABETH SORIANO; SEAN G. TRAPP; JENNY D. VILLENA; TERRY X. WU; BURTON G. CHRISTENSEN; J. KEVIN JUDICE

doi:10.7164/antibiotics.57.326

Hydrophobic Vancomycin Derivatives with Improved ADME Properties

Discovery of Telavancin (TD-6424)

MICHAEL R. LEADBETTER, STACY M. ADAMS, BETTINA BAZZINI, PAUL R. FATHEREE, DANE E. KARR, KEVIN M. KRAUSE, BERNICE M. T. LAM, MARTIN S. LINSELL, MATTHEW B. NODWELL, JOHN L. PACE, KELLY QUAST, JENG-PYNG SHAW, ELIZABETH SORIANO, SEAN G. TRAPP, JENNY D. VILLENA, TERRY X. WU, BURTON G. CHRISTENSEN, J. KEVIN JUDICE

Author information

MICHAEL R. LEADBETTER
Theravance, Inc.
STACY M. ADAMS
Theravance, Inc.
BETTINA BAZZINI
Theravance, Inc.
PAUL R. FATHEREE
Theravance, Inc.
DANE E. KARR
Theravance, Inc.
KEVIN M. KRAUSE
Theravance, Inc.
BERNICE M. T. LAM
Theravance, Inc.
MARTIN S. LINSELL
Theravance, Inc.
MATTHEW B. NODWELL
Theravance, Inc.
Angiotech Pharmaceuticals
JOHN L. PACE
Theravance, Inc.
KELLY QUAST
Theravance, Inc.
JENG-PYNG SHAW
Theravance, Inc.
ELIZABETH SORIANO
Theravance, Inc.
SEAN G. TRAPP
Theravance, Inc.
JENNY D. VILLENA
Theravance, Inc.
TERRY X. WU
Theravance, Inc.
BURTON G. CHRISTENSEN
Theravance, Inc.
J. KEVIN JUDICE
Theravance, Inc.
Department of Medicinal Chemistry, Genentech, Inc.

JOURNAL FREE ACCESS

2004 Volume 57 Issue 5 Pages 326-336

DOI https://doi.org/10.7164/antibiotics.57.326

Details

Abstract

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.

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