Dibenzoxepinone hydroxylamines and hydroxamic acids: dual inhibitors of cyclooxygenase and 5-lipoxygenase with potent topical antiinflammatory activity.

Hydroxylamine and hydroxamic acid derivatives of a known nonsteroidal antiinflammatory dibenzoxepine series display both cyclooxygenase (CO) and 5-lipoxygenase (5-LO) inhibitory properties. Many of these new dual CO/5-LO inhibitors also exhibit potent topical antiinflammatory activity in the arachidonic acid-induced murine ear edema model. On the basis of their promising profile of in vitro and in vivo activities, hydroxamic acids 24h, 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-N-hydroxy-N-++ +methylpropanamide (HP 977), and 25, 3-(6,11-dihydrodibenz[b,e]oxepin-2-yl)-N-hydroxy-N- methylpropanamide (P10294), were selected as developmental candidates for the topical treatment of inflammatory skin disorders.

3-[[(Aryloxy)alkyl]piperidinyl]-1,2-benzisoxazoles as D2/5-HT2 antagonists with potential atypical antipsychotic activity: antipsychotic profile of iloperidone (HP 873).

A series of 3-[[(aryloxy)alkyl]piperidinyl]-1,2-benzisoxazoles was synthesized and evaluated as potential antipsychotic D2/5-HT2 antagonists. Most of these compounds showed potent antipsychotic-like activity in an apomorphine-induced climbing mouse paradigm, with many also showing preferential mesolimbic activity, as indicated by their weaker effects in an apomorphine-induced stereotypy model. In receptor binding assays, many displayed a moderate affinity for the D2 receptor coupled with a significantly greater affinity for the 5-HT2 receptor: a property that has been suggested as necessary for atypicality.

Effects of atypical antipsychotic agents on social behavior in rodents.

There are numerous preclinical screening procedures that are predictive of clinical efficacy for the positive symptoms of schizophrenia but no assays for the negative symptoms such as social withdrawal. In the social interaction test in rats, the atypical antipsychotic drug clozapine (10.0 mg/kg) and two putative atypical agents risperidone (0.

Efforts toward combined analgesic/antidepressants: synthesis and evaluation of (3-aryl-2,3-dihydrobenzofuran-3-yl)alkanamines.

Several (3-aryl-2,3-dihydrobenzofuran-3-yl)alkanamines, designed as potential antidepressant agents with analgesic properties, were synthesized and pharmacologically evaluated. While two compounds (1a, 1f) displayed potent antitetrabenazine activity, concomitant antinociceptive activity in the phenylquinone writhing assay was not observed.

Dibenz[b,e]oxepinalkanoic acids as nonsteroidal antiinflammatory agents. 4. Synthesis and evaluation of 4-(4,10-dihydro-10-oxothieno[3,2-c] [1]benzoxepin-8-yl)butanol and -butyric acid and related derivatives.

4,10-Dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetic acid (6) was previously reported as a potent antiinflammatory-analgesic agent characterized by an impressive therapeutic ratio in comparison with indomethacin. With the goal of finding compounds that might display even more favorable therapeutic ratios and/or enhanced antiinflammatory/analgesic properties in comparison to 6, we synthesized 4-(4,10-dihydro-10-oxothieno [3,2-c][1]-benzoxepin-8-yl) butanol (4b) and -butyric acid (5a) and a series of related derivatives. All compounds were evaluated for potential analgesic activity in the phenylquinone-induced writhing (PQW) assay, for antiinflammatory activity in the carrageenan-induced paw edema (CPE) model and, where warranted, for gastric irritation (GI) liability.