We have previously demonstrated that the prototypical GABA B receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABA B agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABA B agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABA B agonists devoid of classical GABA B agonist related CNS side effects at therapeutic doses and the optimization of this type of compound for inhibition of TLESRs, which has resulted in a candidate drug ( R)- 7 (AZD3355) that is presently being evaluated in man.
We have synthesized two series of liquid crystals, viz. 4'- (w-(2-ethoxy) propoxy)alkoxyphenyl4-alkoxybenzoate, 2, (abbreviated C,-C.-OEt') and 4'-(0-(2-ch1oro)propoxy)alkoxyphenyl 4-alkoxybenzoate, 3, (abbreviated C,-C,-a*). Compounds belonging to the latter mainly exhibit smectic A and B phases while the former show enantiotropic smectic C' at or near room temperature as well as A and smectic phases of higher order. The magnitude of the spontaneous polarization is moderate (-4 nC/cm2). There is no alteration in sign for the spontaneous polarization and for the helical pitch as function of the rz value. The C,-C,-OEt* and C,-C,-OEt* compounds are exhibiting unusually long helical periodicity for a pure compound (30-50 Wm). Compounds of series 2 also show a close relationship between spontaneous polarization and tilt angle giving a practically temperature independent ratio PI@, making the definition of a material constant Po = P / @ meaningful.
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