[Convulsive liability of an oral carbapenem antibiotic, tebipenem pivoxil].

Tebipenem pivoxil (TBPM-PI), the first oral carbapenem antibiotic both in Japan and abroad, was examined on its convulsive liability. We used ICR male mice and Sprague-Dawley male rats to examine the pro-convulsive effect and anticonvulsive effect of TBPM-PI and its active metabolite, TBPM. (1) When mice were treated with TBPM-PI (30-1000 mg/kg, p.o.) or TBPM (10-300 mg/kg, i.v.), no convulsion was noted at any dose level. When rats were treated with TBPM (300 mg/kg, i.v.), no convulsant effects were noted in electroencephalography or behavioral observation. In intraventricular injection of TBPM in mice, clonic convulsion was observed in 7/10 animals at 100 microg but no effect at 30 microg. On the other hand, the administration of 10/10 microg imipenem/cilastatin (IPM/CS) resulted in clonic convulsion in all animals and tonic convulsion in 3/10 animals, and 4/10 animals died. The administration of 100 microg meropenem did not cause any effects. (2) When mice were co-administered with pentylenetetrazole (45 mg/kg: maximum dose level at which no convulsion is induced) and TBPM-PI (30-300 mg/kg, p.o.) or TBPM (300 mg/kg, i.v.), convulsion enhancing effect was not noted. On the other hand, the co-administration of pentylenetetrazole with IPM/CS (300/300 mg/kg, i.v.) enhanced a convulsive effect of pentylenetetrazole. (3) When mice were treated with TBPM-PI (30-300 mg/kg, p.o.) or TBPM (100 mg/kg, i.v.), inhibitory effect was not noted on convulsions induced by electrostimulation, pentylenetetrazole or strychinine. In conclusion, there were no pro-convulsive effects or anticonvulsive effect in the oral administration of TBPM-PI or intravenous administration of TBPM. Pro-convulsive effect was observed in the intraventricular injection of TBPM as in the case of other carbapenem antibiotics, but such action was weaker than that in IPM/CS administration. Accordingly, the risk of occurrence of convulsion related to TBPM-PI administration was low compared to IPM/CS administration, and TBPM-PI was considered to be less potential to induce convulsions in clinical use.

Nonsteroidal progesterone receptor ligands (II); synthesis and SAR of new tetrahydrobenzindolone derivatives.

The human progesterone receptor (PR) binding affinity and the PR agonistic or antagonistic potency of tetrahydronaphthofuranone derivatives were shown previously to be markedly influenced by substituents at the 6- and 7-positions. Here, we synthesized tetrahydrobenzindolones possessing a lactam ring, which enabled us to modify the 6- and 7-positions more freely, since tetrahydrobenzindolones are chemically more stable than tetrahydronaphthofuranones. The tetrahydrobenzindolone derivatives generally showed higher PR binding affinity than the corresponding tetrahydronaphthofuranones. We also succeeded in separating the agonistic and antagonistic activities by choosing suitable substituent groups at the 6- and/or 7-position(s) of the tetrahydrobenzindolone. The effects of representative agonists, 12c (CP8668), and 14a (CP8816), and a representative antagonist, 15f (CP8661), were confirmed in in vivo tests. In this report, we mainly describe the synthesis and structure-activity relationships (SAR) of tetrahydrobenzindolone derivatives, as new nonsteroidal PR ligands.