Steroid 5α-Reductase: Comparative Study of Mechanism of Inhibition by Nonsteroids ONO-3805 and LY191704

Harris, G.; Ellsworth, Kenneth; Witzel, B. E.; Tolman, Richard L.

doi:10.1006/bioo.1996.0033

Cited by 4 publications

(3 citation statements)

References 18 publications

(26 reference statements)

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“…Kinetics are in agreement with formation of a dead end complex between the inhibitor and the enzyme-NADP + complex remaining after release of DHT (Eqn. 3 87 ), the tendency for this to occur presumably being due to their negative charge. Synergism exists between binding of the inhibitor and NADP + in support of this view.…”

Section: Steroidal Inhibitorsmentioning

confidence: 99%

“…Synergism exists between binding of the inhibitor and NADP + in support of this view. 87 Epristeride 136 (R 1 =H, R 2 =Bu t ) is a selective 5 -SR2 inhibitor (K i =0.7-2 n) with little effect on 5 -SR1 (400-450 n) and seven related steroidogenic oxido-reductases. 87 A theoretical advantage of an uncompetitive inhibitor is that the associated rise in the testosterone level on inhibition does not reverse the extent of inhibition as may be the case for competitive inhibition.…”

Section: Steroidal Inhibitorsmentioning

confidence: 99%

“…87 Epristeride 136 (R 1 =H, R 2 =Bu t ) is a selective 5 -SR2 inhibitor (K i =0.7-2 n) with little effect on 5 -SR1 (400-450 n) and seven related steroidogenic oxido-reductases. 87 A theoretical advantage of an uncompetitive inhibitor is that the associated rise in the testosterone level on inhibition does not reverse the extent of inhibition as may be the case for competitive inhibition. However since epristeride is less effective in reducing DHT levels in vivo than finasteride this advantage is not apparent.…”

Section: Steroidal Inhibitorsmentioning

confidence: 99%

See 2 more Smart Citations

Inhibitors of enzymes of androgen biosynthesis: cytochrome P45017α and 5α-steroid reductase

Jarman¹,

Hj²,

Pj³

et al. 1998

Nat. Prod. Rep.

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Section: Steroidal Inhibitorsmentioning

confidence: 99%

Section: Steroidal Inhibitorsmentioning

confidence: 99%

Section: Steroidal Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

Inhibitors of enzymes of androgen biosynthesis: cytochrome P45017α and 5α-steroid reductase

Jarman¹,

Hj²,

Pj³

et al. 1998

Nat. Prod. Rep.

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De Sign and Synthesis of 1,2,4‐Oxadiazole Derivatives as Non‐Steroidal 5α‐Reductase Inhibitors

Chang

Kan

Chen

et al. 2002

J Chinese Chemical Soc

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The pur pose of this study was to syn the size com pounds in which the 1,2,4-oxadiazole moi ety re placed the am ide bond of ONO3805 and to eval u ate its 5 -reductase in hib i tory ac tiv ity as a po ten tial be nign prostatic hy per pla sia ther a peu tic tar get. Four 1,2,4-oxadiazole de riv a tives, 1, 2, 8, and 20, were eval u ated in vi tro against 5 -reductase of rat liver microsome. The pre pared 1 and 2 pos sessed sim i lar bind ing af fin ity (Ki) to that of ONO3805. There fore, the use of 1,2,4-oxadiazole ring as sur ro gate of the am ide bond in ONO3805 has a suc cess ful re sult in this study. It leads not only to en hance chem i cal sta bil ity but also to main tain mean ing ful in hib i tory ac tiv ity. The bu tyric acid moi ety of these in hib i tors is con sid ered to play an im por tant role in mimicing the phos pho ric acid por tion of coenzyme-NADPH in in ter act ing with the ac tive site of 5 -reductase. IN TRO DUC TIONSte roid 5 -reductase is a mem brane-associated enzyme, which cat a lyzes the re duc tion of tes tos ter one to the bio log i cally more ac tive dihydrotestosterone (DHT) in the pres ence of NADPH.1 El e vated DHT has been im pli cated as a caus ative fac tor of skin dis or ders and be nign pros tatic hy perpla sia (BPH). 2 There fore, in hi bi tion of 5 -reductase is an attrac tive tar get for ther a peu tic in ter ven tion in dis or ders as soci ated with el e vated lev els of DHT such as BPH, 3,4 acne, 5 male pat tern bald ness, 6 and hirsutism. 7 A num ber of 5 -reductase in hib i tors have been re ported, in clud ing both steroidal 8 and nonsteroidal in hib i tors. 9 Starting our re search pro gram to find a new 5 -reductase in hib i tor, we fo cused our at ten tion on the de vel op ment of novel nonsteroidal compounds, es pe cially ONO3805. Ac cord ing to the bioiso s terism, 10 some re search groups have suc cess fully re placed the es ter or am ide group of bi o log i cally ac tive com pounds by an 1,2,4-oxadiazole moi ety to im prove in vivo ef fi cacy. 11 The intramolecular acid cat a lyzed the hy dro ly sis of the am ide bond 1 2,13 even though the hy dro ly sis ex hib its a half-life of 7 years un der neu tral con di tions and at room tem per a ture. 14 In ad di tion, we found that the am ide bond of ONO3805 was partially cleaved in a DMSO-d6 so lu tion at 37 o C in four months.Re place ment of the am ide bond with a 1,2,4-oxadiazole ring for in creas ing hydrolytic re sis tance, 1 5 met a bolic sta bil ity, and im prov ing pharmacokinetic per for mance 16 has been reported. Herein, de riv a tives with 1,2,4-oxadiazole sur ro gate of the am ide bond in ONO3805 as po ten tial 5 -reductase inhib i tors were de signed and syn the sized (Fig. 1). RE SULTS AND DIS CUS SIONThe syn the sis of tar get com pound 1 is il lus trated in

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5Α-Reductase inhibitory tannin-related compounds isolated from Shorea laeviforia

2003

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Steroid 5α-Reductase: Comparative Study of Mechanism of Inhibition by Nonsteroids ONO-3805 and LY191704

Cited by 4 publications

References 18 publications

Inhibitors of enzymes of androgen biosynthesis: cytochrome P45017α and 5α-steroid reductase

Inhibitors of enzymes of androgen biosynthesis: cytochrome P45017α and 5α-steroid reductase

De Sign and Synthesis of 1,2,4‐Oxadiazole Derivatives as Non‐Steroidal 5α‐Reductase Inhibitors

5Α-Reductase inhibitory tannin-related compounds isolated from Shorea laeviforia

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