Synthesis of water-soluble prodrugs of BMS-191011: a maxi-K channel opener targeted for post-stroke neuroprotection.
A variety of water-soluble prodrugs of BMS-191011 was synthesized and evaluated for solution state stability and rate of conversion to BMS-191011 in rat and human plasma. The deoxycarnitine ester prodrug (11c) was selected for clinical evaluation based on its superior chemical stability, crystallinity and cleavage to BMS-191011 in human plasma.
Department of Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. hewawasp@bms.com
Piyasena
P
Hewawasam
Min
M
Ding
Nathan
N
Chen
Dalton
D
King
Jay
J
Knipe
Lorraine
L
Pajor
Astrid
A
Ortiz
Valentin K
VK
Gribkoff
John
J
Starrett
D000818:Animals; D001622:Betaine / Q000031:analogs & derivatives*; D001769:Blood / Q000378:metabolism; D002331:Carnitine; D003460:Crystallization; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics*; D010069:Oxadiazoles; D015221:Potassium Channels / Q000819:agonists*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D012995:Solubility; D020521:Stroke / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014867:Water
C480883:3-((5-chloro-2-hydroxyphenyl)methyl)-5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2(3H)-one; D006575:Heterocyclic Compounds, 3-Ring; D018696:Neuroprotective Agents; D010069:Oxadiazoles; D015221:Potassium Channels; D011355:Prodrugs; D014867:Water; D001622:Betaine; C002889:gamma-butyrobetaine; D002331:Carnitine