ABSTRACT
Compound 8a (BMS-191011), an opener of the cloned large-conductance, Ca2+-activated potassium (maxi-K) channel, demonstrated efficacy in in vivo stroke models, which led to its nomination as a candidate for clinical evaluation. Its maxi-K channel opening properties were consistent with its structural topology, being derived by combining elements from other known maxi-K openers. However, 8a suffered from poor aqueous solubility, which complicated elucidation of SAR during in vitro evaluation. The activity of 8a in in vivo stroke models and studies directed toward improving its solubility are reported herein. Enhanced solubility was achieved by appending heterocycles to the 8a scaffold, and a notable observation was made that inclusion of a simple amino group (anilines 8k and 8l) yielded excellent in vitro maxi-K ion channel opening activity and enhanced brain-to-plasma partitioning compared to the appended heterocycles.
Subject(s)
Large-Conductance Calcium-Activated Potassium Channels/physiology , Oxadiazoles/pharmacology , Animals , Brain/metabolism , Crystallography, X-Ray , Female , In Vitro Techniques , Ion Channel Gating , Molecular Structure , Oocytes/drug effects , Oocytes/physiology , Oxadiazoles/chemistry , Oxadiazoles/pharmacokinetics , Patch-Clamp Techniques , Plasma , Rats , Rats, Inbred SHR , Solubility , Stroke/drug therapy , Stroke/pathology , Structure-Activity Relationship , Xenopus laevisABSTRACT
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.
Subject(s)
Betaine/analogs & derivatives , Carnitine , Heterocyclic Compounds, 3-Ring/chemical synthesis , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/pharmacokinetics , Potassium Channels/agonists , Prodrugs/chemical synthesis , Prodrugs/metabolism , Stroke/drug therapy , Animals , Blood/metabolism , Crystallization , Dose-Response Relationship, Drug , Drug Stability , Heterocyclic Compounds, 3-Ring/metabolism , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Humans , Neuroprotective Agents/metabolism , Oxadiazoles , Prodrugs/pharmacokinetics , Rats , Solubility , Structure-Activity Relationship , WaterABSTRACT
3-Aryl-3-fluorooxindoles can be efficiently synthesized in two steps by the addition of an aryl Grignard to an isatin, followed by treatment with DAST. Oxindole 1 (BMS-204352; MaxiPost) can be isolated using chiral HPLC or prepared by employing chiral resolution. Cloned maxi-K channels are opened by 1, which demonstrates a brain/plasma ratio >9 in rats.
