Cook C E, Wani M C, Jump J M, Lee Y W, Fail P A, Anderson S A, Gu Y Q, Petrow V
Research Triangle Institute, North Carolina 27709-2194.
J Med Chem. 1995 Mar 3;38(5):753-63. doi: 10.1021/jm00005a003.
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.
已合成了(4aRS,5SR,9bRS)-2-乙基-2,3,4,4a,5,9b-六氢-7-甲基-5-对甲苯基-1H-茚并[1,2-c]吡啶（桑多兹20-438, 10a；R1 = 乙基，R2 = R3 = 甲基，R4 = H）的类似物，并在小鼠中测试了它们减轻睾丸重量和破坏精子发生的能力。活性强烈依赖于立体异构和手性，这与涉及与特定大分子相互作用的作用机制一致。它受氮取代基变化的影响，最显著的是受5-芳基环对位取代基变化的影响。氢、氟、羟基或甲氧基取代导致活性丧失，而甲基（桑多兹20-438, 10a）、羧酸盐（RTI-4587-054, 10k；R1 = 乙基，R2 = 甲基，R3 = COOH，R4 = H）、酯（RTI-4587-056, 12b；R1 = 乙基，R2 = 甲基，R3 = COOMe，R4 = H）、甲酰基（RTI-4587-030, 12i；R1 = 乙基，R2 = 甲基，R3 = CHO，R4 = H）或羟甲基（RTI-4587-055, 12g；R1 = 乙基，R2 = 甲基，R3 = CH2OH，R4 = H）基团产生抗精子发生化合物。甲酯12b是一种有效的抗生育剂，当以7-15 mg/kg的剂量每日口服给予雄性小鼠35天时，对交配无明显影响。对这些化合物作为男性避孕药和精子发生研究探针进行进一步评估似乎是有必要的。
