Structure-activity studies of 2,3,4,4a,5,9b-hexahydroindeno[1,2-c]pyridines as antispermatogenic agents for male contraception.
Analogs of (4aRS,5SR,9bRS)-2-ethyl-2,3,4,4a,5,9b-hexahydro-7-meth yl-5-p- tolyl-1H-indeno[1,2-c]pyridine (Sandoz 20-438, 10a; R1 = ethyl, R2 = R3 = methyl, R4 = H) have been synthesized and tested in mice for their ability to reduce testes weight and disrupt spermatogenesis. The activity was strongly dependent on stereoisomerism and chirality, consistent with a mechanism of action involving interaction with a specific macromolecule. It was affected by changes in the nitrogen substituent and most strikingly by changes in the p-substituent of the 5-aryl ring. A hydrogen, fluorine, hydroxy, or methoxy substituent led to loss of activity, whereas methyl (Sandoz 20-438, 10a), carboxylate (RTI-4587-054, 10k; R1 = ethyl, R2 = methyl, R3 = COOH, R4 = H), ester (RTI-4587-056, 12b; R1 = ethyl, R2 = methyl, R3 = COOMe, R4 = H), formyl (RTI-4587-030, 12i; R1 = ethyl, R2 = methyl, R3 = CHO, R4 = H), or hydroxymethyl (RTI-4587-055, 12g; R1 = ethyl, R2 = methyl, R3 = CH2OH, R4 = H) groups resulted in antispermatogenic compounds. Methyl ester 12b was an effective antifertility agent, without apparent effects on mating, when given orally to male mice at 7-15 mg/kg daily for 35 days. Further evaluation of these compounds as male contraceptive agents and probes for study of spermatogenesis appears warranted.
Cook
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Research Triangle Institute, North Carolina 27709-2194.
Wani
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Jump
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Lee
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Fail
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Anderson
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Gu
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Petrow
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D000284:Administration, Oral; D000818:Animals; D000988:Antispermatogenic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D005298:Fertility / Q000187:drug effects; D007279:Injections, Subcutaneous; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013737:Testis / Q000187:drug effects
D000988:Antispermatogenic Agents; D011725:Pyridines; C042923:2,3,4,4a,5,9b-hexahydro-1H-indeno(1,2-b)pyridine