Optimization of halopemide for phospholipase D2 inhibition.
Halopemide, which was identified by HTS to inhibit phospholipase D2 (PLD2), provided the basis for an exploratory effort to identify potent inhibitors of PLD2 for use as inflammatory mediators. Parallel synthesis and purification were utilized to rapidly identify orally available amide analogs derived from indole 2-carboxylic acids with superior potency versus PLD2.
Monovich
Lauren
L
Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA. lauren.monovich@novartis.com
Mugrage
Benjamin
B
Quadros
Elizabeth
E
Toscano
Karen
K
Tommasi
Ruben
R
LaVoie
Stacey
S
Liu
Eugene
E
Du
Zhengming
Z
LaSala
Daniel
D
Boyar
William
W
Steed
Paul
P
D000284:Administration, Oral; D000577:Amides; D000818:Animals; D000893:Anti-Inflammatory Agents; D004294:Domperidone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics; D020128:Inhibitory Concentration 50; D010599:Pharmacokinetics; D010739:Phospholipase D / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship
D000577:Amides; D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D004294:Domperidone; C017357:halopemide; D010739:Phospholipase D