Exploring the positional attachment of glycopeptide/beta-lactam heterodimers.
Further investigations towards novel glycopeptide/beta-lactam heterodimers are reported. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons, 4, 2, 5 and 10, 18, 25 respectively, were chemically linked to yield heterodimer antibiotics. These novel compounds were designed to inhibit Gram-positive bacterial cell wall biosynthesis by simultaneously targeting the principal cellular targets of both glycopeptides and beta-lactams. The positional attachment of both the vancomycin and the cephalosporin central cores has been explored and the SAR is reported. This novel class of bifunctional antibiotics 28-36 all displayed remarkable potency against a wide range of Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). A subset of compounds, 29, 31 and 35 demonstrated excellent bactericidal activity against MRSA (ATCC 33591) and 31 and 35 also exhibited superb in vivo efficacy in a mouse model of MRSA infection. As a result of this work compound 35 was selected as a clinical candidate, TD-1792.
Long
Daniel D
DD
Theravance, Inc., San Francisco, CA 94080, USA. dlong@theravance.com
Aggen
James B
JB
Chinn
Jason
J
Choi
Seok-Ki
SK
Christensen
Burton G
BG
Fatheree
Paul R
PR
Green
David
D
Hegde
Sharath S
SS
Judice
J Kevin
JK
Kaniga
Koné
K
Krause
Kevin M
KM
Leadbetter
Michael
M
Linsell
Martin S
MS
Marquess
Daniel G
DG
Moran
Edmund J
EJ
Nodwell
Matthew B
MB
Pace
John L
JL
Trapp
Sean G
SG
Turner
S Derek
SD
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002511:Cephalosporins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019281:Dimerization; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D005260:Female; D006020:Glycopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006094:Gram-Positive Bacteria / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D047090:beta-Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014640:Vancomycin
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D006020:Glycopeptides; D047090:beta-Lactams; C539430:cefilavancin; D014640:Vancomycin