1-Halobenzyl-1H-indazole-3-carboxylic acids. A new class of antispermatogenic agents

Corsi, G. B.; Palazzo, G; C, Germani; Barcellona, P. Scorza; Silvestrini, Bruno

doi:10.1021/jm00228a008

Cited by 122 publications

(48 citation statements)

References 4 publications

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“…One of the most potent compounds in a new class of antispermatogenic agents [3], 1-(2,4-dichlorobenzyl)-lH-indazole- 3-carboxylic acid (DICA, AF 1890; Fig. 1) is remarkably nontoxic (oral LD,, > 2 g/kg body weight) and free of serious side effects in the rat.…”

Section: Introductionmentioning

confidence: 99%

1-(2,4-Dichlorobenzyl)-1 H-lndazole-3-Carboxylic Acid (DICA), an Exfoliative Antispermatogenic Agent in the Rat

Lobl¹

1979

Archives of Andrology

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The oral administration of 50 mg DICNkg at nine weekly or four monthly intervals produced partially reversible infertility in male rats as judged by the results of serial mating and testicular histology. Oral 500 mg DICNkg doses administered at the same intervals produced permanent sterility. Single oral doses of 50 or 500 mg DICMkg elevated mean FSH concentrations on days 2, 3, and 7 but did not affect LH or testosterone. Mean plasma concentration peaked at 74 pghl 4 hr after a 50 mg/kg dose of uniformly tritiated DICA; 24 hr later, it had declined rapidly to 5.5 &ml. The drug did not have a strong affinity for any tissue studied including the testis. DICA-induced exfoliation of immature germ cells was first observed 4 hr after administration and led to significantly reduced testis weights by day 2. Neither single doses of 10-250 mg DICNkg nor five daily doses of 10-100 mg DICMkg reduced seminal vesicle, ventral prostate, or body weights of male rats. Chronic weekly DICA administration did reduce mean seminal vesicle weight. These studies have shown that DICA is an effective, partially reversible antifertility agent that directly affects the rat testis.

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Section: Introductionmentioning

confidence: 99%

1-(2,4-Dichlorobenzyl)-1 H-lndazole-3-Carboxylic Acid (DICA), an Exfoliative Antispermatogenic Agent in the Rat

Lobl¹

1979

Archives of Andrology

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“…Lonidamine or 1-[(2,4-dichlorophenyl)methyl]-1H-indazole-3-carboxylic acid is the most potent derivative of a series of indazole carboxylic acids which originally aroused interest on account of their anti-spermatogenic activity observed at very low doses in comparison with those producing general toxicity (Corsi et al, 1976). It has also been reported that the potency of anti-spermatogenic activity varies ten-fold between the different members of this series without any parallel changes in their general toxicity .…”

mentioning

confidence: 99%

Effects of lonidamine alone or combined with hyperthermia in some experimental cell and tumour systems

Silvestrini¹,

Hahn²,

Cioli³

et al. 1983

Br J Cancer

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Summary Lonidamine or 1-[(2, 4-dichlorophenyl) methyl]-lH-indazole-3-carboxylic acid, studied in a battery of in vitro and in vivo tests currently used for the screening of anti-tumour agents affecting cell division, has been shown to have a narrow spectrum of anti-tumour activity. The significance of this finding is discussed in the light of previous investigations suggesting that lonidamine affects mitochondrial function and not cell replication. Hyperthermia has been shown to sensitize tumour cells to lonidamine. This observation indicates that in combination with hyperthermia lonidamine has some potential for the treatment of cancer; moreover, it suggests that hyperthermia might reproduce a metabolic condition occurring in some stages of the disease. The blood levels corresponding to the anti-tumour action of lonidamine in animals are in the range of those detected in patients treated with the drug.

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“…Similarly, in the female monkey BUN became elevated following 500 mg/kg doses of DICA but declined to normal by 2 weeks after the last dose. A survey of several analogues of DICA [2] showed that different compounds with equal antispermatogenic potency induced different elevations in serum BUN. The analogue study suggested that it might be possible to separate the kidney activity from the antifertility activity.…”

Section: Discussionmentioning

confidence: 99%

“…) is one of the most potent compounds in a new class of antispermatogenic agents [2]. The compound is not very toxic in the rat (LD5, -, 2 2 g/kg) and is efficacious when administered weekly or monthly [ 1 I].…”

Section: -(24-dichlorobenzyl)-lh-indazole-3-carboxylic Acid (Af1890mentioning

confidence: 99%

Characterization of the exfoliative antispermatogenic agent 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid in the rhesus monkey

Lobl¹,

Forbes²,

Kirton³

et al. 1979

Archives of Andrology

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The effects of oral doses of 1-(2,4-dichlorobenzyI)-1H-indazole-3-carboxylic acid (DICA) on spermatogenesis in the rhesus monkey (Macaca rnulatta) was studied. Four animals given five daily 50 mdkg doses or three or five daily 500 mgkg doses showed that DICA was an exfoliating antispermatogenic compound. The inhibition of spermatogenesis was only partially reversible following 500 mg/kg doses of DICA. Weekly and monthly 50 mgkg doses of DICA only partially inhibited spermatogenesis as measured by electro-ejaculated sperm counts. Response in individual monkeys ranged from azoospermia to no effect. Testicular biopsies confirmed this finding. DICA did not affect serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), or testosterone concentrations. The blood absorption or urinary excretion rates of uniformly tritiated DICA in the animals that responded well did not differ from those monkeys that responded poorly. DICA metabolites were not detected in monkey urine. Serum testosterone concentrations appeared to vary with the season of the year, but FSH concentrations and ejaculated sperm count did not.

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1-Halobenzyl-1H-indazole-3-carboxylic acids. A new class of antispermatogenic agents

Cited by 122 publications

References 4 publications

1-(2,4-Dichlorobenzyl)-1 H-lndazole-3-Carboxylic Acid (DICA), an Exfoliative Antispermatogenic Agent in the Rat

1-(2,4-Dichlorobenzyl)-1 H-lndazole-3-Carboxylic Acid (DICA), an Exfoliative Antispermatogenic Agent in the Rat

Effects of lonidamine alone or combined with hyperthermia in some experimental cell and tumour systems

Characterization of the exfoliative antispermatogenic agent 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid in the rhesus monkey

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