Discovery of potent selective bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model. Part II: optimization studies and demonstration of in vivo efficacy.

Selective phosphodiesterase 2 (PDE2) inhibitors are shown to have efficacy in a rat model of osteoarthritis (OA) pain. We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of phosphodiesterase 4 (PDE4) inhibitors, while minimizing PDE4 inhibitory activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like binding mode orthogonal to the cAMP-like binding mode found in PDE4. Extensive structure activity relationship studies ultimately led to identification of pyrazolodiazepinone, 22, which was >1000-fold selective for PDE2 over recombinant, full length PDEs 1B, 3A, 3B, 4A, 4B, 4C, 7A, 7B, 8A, 8B, 9, 10 and 11. Compound 22 also retained excellent PDE2 selectivity (241-fold to 419-fold) over the remaining recombinant, full length PDEs, 1A, 4D, 5, and 6. Compound 22 exhibited good pharmacokinetic properties and excellent oral bioavailability (F=78%, rat). In an in vivo rat model of OA pain, compound 22 had significant analgesic activity 1 and 3h after a single, 10 mg/kg, subcutaneous dose.

Discovery of potent, selective, bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model, part I: transformation of selective pyrazolodiazepinone phosphodiesterase 4 (PDE4) inhibitors into selective PDE2 inhibitors.

We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of PDE4 inhibitors, while simultaneously minimizing PDE4 activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like mode in contrast to the cAMP-like binding mode found in PDE4. Structure activity relationship studies coupled with an inhibitor bound crystal structure in the active site of the catalytic domain of PDE2 identified structural features required to minimize PDE4 inhibition while simultaneously maximizing PDE2 inhibition.

Comparison of cyclophosphamide and diaziquone in a retinoblastoma xenograft model.

The benefits and optimal applications of chemotherapy in the management of retinoblastoma remain to be defined. There are major obstacles to its further study in the clinical setting. A xenograft model of human retinoblastoma heterotransplanted directly into the anterior chamber of the nude mouse eye has been adapted for evaluation of therapeutic efficacy. Cyclophosphamide, the most effective conventional drug, and diaziquone, an experimental agent, both produced documented and comparable responses in each of four xenograft cell lines. There was no evidence of rapidly emerging drug resistance or cross-resistance between two agents when sequential chemotherapy courses were given. Diaziquone is an effective chemotherapeutic agent for retinoblastoma in the xenograft model, and may have applications in clinical management.

Phase II study of diaziquone in untreated advanced gastric carcinoma. A Southwest Oncology Group Study.

Twenty-nine patients with a diagnosis of advanced adenocarcinoma of the stomach with gross unresectable or measurable residual disease and no prior therapy were entered into a study utilizing diaziquone (AZQ) in an intermittent 3-week schedule of 40 mg/m2. Of 28 eligible patients, 1 (4%) experienced a partial response, 7 (25%) had stable disease of no response, and 18 (64%) developed increasing disease. Two (7%) were unevaluable. Median survival was 3.8 months. Major toxicities were myelosuppression and gastrointestinal, 11 of which were considered to be life-threatening. AZQ used as a single intermittent agent appears to have no significant activity to warrant use in untreated advanced gastric carcinoma. However, recognizing the short plasma half-life of AZQ, significant responses by other schedules of administration are not precluded.

Evaluation of spin labeled TEPA and CCNU analogs against osteosarcoma and MNU-induced mammary carcinoma of the SD-rat.

The effectiveness to reduce tumor growth by 1-(2-chloroethyl)-3-(1-oxyl-2,2,6,6-tetramethylpiperidinyl)- 1-nitrosourea (SLCNU) and N,N,N,'N'- bis(1,2-ethanediyl)-N"-(1-oxyl-2,2,6,6-tetramethyl- 2-piperidinylaminocarbonyl)-phosphoric triamide (SLDU) was studied in osteosarcoma and MNU-induced mammary carcinoma in the SD-rat. Both compounds elicited neither an inhibitory effect on these tumors nor an increase in the mean/median life span as compared to the control group.

A phase I/II study of 24 hour intravenous AZQ in recurrent primary brain tumors.

This study was undertaken to determine the maximum tolerated dose of aziridinylbenzoquinone (AZQ) given as a 24-hour intravenous infusion every 21-28 days. Thirty-four patients with recurrent or progressive gliomas received AZQ at a dose of 25, 30, 35, 40, or 45 mg/m2. At a dose of 45 mg/m2, leukopenia and thrombocytopenia of grade 3 or greater was observed in 42% and 25% of patients respectively; no patient required transfusion or antibiotics for fever. For administration of AZQ at a 24-hour intravenous infusion, we recommend a starting dose of 40 mg/m2 for patients without previous exposure to cytotoxic agents, and 35 mg/m2 for patients treated with such agents. In 14 patients with glioblastoma, tumor regression was observed in 1 patient (14%) and stabilization of disease was demonstrated in 7 patients (50%). In 17 patients with anaplastic astrocytomas there were no responses, but 8 patients (47%) stabilized. Of two patients with an oligodendroglioma, one continues without progression at 34 weeks after initial response. One patient with malignant ependymoma stabilized and had not progressed at 39 weeks. The median time to tumor progression in patients who stabilized and responded was 18 weeks for those with glioblastoma multiforme and 16 weeks in those with anaplastic astrocytomas.

A phase II clinical trial of diaziquone in the treatment of patients with recurrent endometrial carcinoma. A Gynecologic Oncology Group study.

Twenty-six patients with measurable endometrial cancer refractory to standard therapy received AZQ [1,4-cyclohexadiene-1,4-dicarbamic acid, 2,5-bis(1-aziridinyl)3,6,dioxo,diethyl ester, NSC 182986] 22.5 mg/m2 diluted in 150 ml normal saline intravenously every three weeks. Thirteen patients experienced no toxicity and the dose in those patients was increased to 30 mg/m2 after the first course. The median number of courses given was 2.5 (range 1-9). The leukocyte count fell below 3000/microliter in 12 patients, and below 1000/microliter in two. The platelet count fell below 100,000/microliter in 12 patients, and below 25,000/microliter in one. Cumulative hematologic toxicity was not seen. One clinical complete response and one partial response were observed. Eight patients had stable disease. Median time to disease progression was 2 months. Median survival was 5.9 months. At this dose and schedule AZQ does not appear to have significant activity in recurrent endometrial cancer.

Response rate and toxicity with aziridinylbenzoquinone in patients with recurrent gliomas. A progress report.

Aziridinylbenzoquinone (AZQ), a quinone-containing lipophilic alkylating agent with molecular properties allowing for good penetration through the blood-brain barrier into the central nervous system, was evaluated in a phase II trial for recurrent gliomas patients. Twenty-four patients with computed tomography (CT) scan measurable disease were entered into the trial and received AZQ in doses of a weekly infusion of 15 mg/m2 (group A) and 17.5 mg/m2 (group B). Twenty-two patients were evaluable for both response and toxicity. There were no complete responses in this study. Partial response rates of 23% (3/13) and 11% (1/9) were achieved in group A and group B patients, for a median duration of response of 35 (range 10-106 weeks) and 19 weeks, respectively. The disease was stabilized in five patients from group A and in four patients from group B. Toxicity was mainly hematologic.

Influence of ciamexon on blood glucose and insulin requirement in newly manifested type I diabetics. Results of a pilot study.

Treatment with the selectively immunomodulatory drug 1-[2-methoxy-6-methyl-3-pyridinyl)methyl]-2-aziridine-carbonitrile (ciamexon, BM-42332), an aziridine derivative, of newly diagnosed type I diabetic patients is reported. In an open pilot study the treatment of Cx led to the independence of insulin in 33.3% of the treated patients.

[An anticancer drug--carboquone].

Carboquone (CQ) is an anticancer alkylating agent synthesized and developed by Arakawa et al. (Sankyo Co, Ltd.) in 1970, having chemical structure, 2,5-bis-(1-aziridinyl)-3-(2-carbamoyloxy-1-methoxyethyl)-6-methyl- 1,4- benzoquinone. The antitumor efficacies of CQ were reported as excellent, however, the side effects are considerably strong. For the purpose to increase the effectiveness and to eliminate the side effect, various treatment regimen with CQ have been reported. Combination chemotherapies including CQ and cis-Platinum etc. have been reported to increase the antineoplastic activity and CQ combined with immunopotentiator or prednisone have been reported to diminish the side effects. The regimens of PPQ therapy in our department is as follows. CQ is given 7 mg/m2 iv on day 1; cis-Platinum 20 mg/body, drip infusion on day 1-5. Prednisone 3.0 mg p.o. on day 1-5. The response rate found in this regimen was about 30% so far. Antitumor spectrum of this drug has been reported to become broad.

Azimexone and cysteine hydrazide in the treatment of allergic encephalomyelitis.

In the course of allergic encephalomyelitis (EAE) in chickens, azimexone suppressed the production of the specific IgM immunoglobulins. Moreover, it decreased the level of haptoglobin and sialic acid but stimulated the activity of antitrypsin. It was also observed to reduce the production of the plasmatic cells in the spleen. L-cysteine hydrazide hydrochloride decreased the level of sialic acid in EAE; intensified the activity of trypsin inhibitor and exerted no effect upon the level of antimyelin antibodies.

Treatment of metastatic breast cancer with AZQ: a phase II trial.

Seventeen patients with metastatic breast cancer who had failed prior chemotherapy were treated with intravenous AZQ at a dose of 15-20 mg/m2 weekly for four consecutive weeks followed by a two-week rest period. No responses were observed. Myelosuppression was the dose-limiting toxicity. One patient experienced massive liver infarction possibly related to AZQ. Our data suggest that this agent at the schedule and dosage used is of no benefit in pretreated breast cancer patients.

[Biological effects of leakadin]. / Biologicheskie éffekty leakadina.

57 patients with disseminated tumors of various sites received 10 daily doses of 600 mg/m2 leakadin intravenously. The immunostimulating effect was observed (OKT4/OKT8 normalization). The data on leakadin pharmacokinetics are discussed.

A phase II study of diaziquone in childhood leukemia: a report from the Children's Cancer Study Group.

Diaziquone (aziridinylbenzoquinone, AZQ) was given by 30-min infusion at 25 mg/m2/day on a daily x 5 schedule to 16 children with acute lymphoblastic leukemia (ALL) in bone marrow relapse, 16 children with acute nonlymphocytic leukemia (ANLL) in bone marrow relapse, and 1 child with chronic myelocytic leukemia in blast crisis. None of the children achieved bone marrow remission. Five children (four with ALL and one with ANLL) were also evaluable for the response of central nervous system leukemia; all had a significant reduction in the cerebrospinal fluid blast count. Mild transient transaminase elevation was commonly seen. Grade 3 and 4 hyperbilirubinemia was seen in association with sepsis. AZQ was ineffective for induction of bone marrow remission as utilized in this study.