Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates.
Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates.
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DOI：
10.1021/acs.jmedchem.2c01133
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发表时间：
2022-11-24
影响因子：
7.3
通讯作者：
Meinke, Peter T.
中科院分区：
文献类型：
--
作者：
Miller, Michael;Rossetti, Thomas;Ferreira, Jacob;Ghanem, Lubna;Balbach, Melanie;Kaur, Navpreet;Levin, Lonny R.;Buck, Jochen;Kehr, Maria;Coquille, Sandrine;Heuvel, Joop van den;Steegborn, Clemens;Fushimi, Makoto;Finkin-Groner, Efrat;Myers, Robert W.;Kargman, Stacia;Liverton, Nigel J.;Huggins, David J.;Meinke, Peter T.
可溶性腺苷酸环化酶（sAC：ADCY10）是参与细胞内信号传导的酶。抑制sAC在许多领域具有潜在的治疗效用。例如，sAC对于成功的男性生育力是不可或缺的：sAC激活是精子运动力和经历顶体反应的能力所必需的，这两个过程对卵母细胞受精至关重要。现有sAC抑制剂作为按需非激素男性避孕药的药理学评价表明，高内在效力、快速和缓慢解离速率是成功应用男性避孕药的基本设计要素。在本文所述的药物化学活动过程中，我们确定了满足这些标准并适用于多种sAC药理学体内评价的sAC抑制剂。
Soluble adenylyl cyclase (sAC: ADCY10) is an enzyme involved in intracellular signaling. Inhibition of sAC has potential therapeutic utility in a number of areas. For example, sAC is integral to successful male fertility: sAC activation is required for sperm motility and ability to undergo the acrosome reaction, two processes central to oocyte fertilization. Pharmacologic evaluation of existing sAC inhibitors for utility as on-demand, nonhormonal male contraceptives suggested that both high intrinsic potency, fast on and slow dissociation rates are essential design elements for successful male contraceptive applications. During the course of the medicinal chemistry campaign described here, we identified sAC inhibitors that fulfill these criteria and are suitable for in vivo evaluation of diverse sAC pharmacology.
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DOI：
10.1073/pnas.0400050101
发表时间：
2004-03-02
影响因子：
11.1
作者：
Esposito, G;Jaiswal, BS;Gossen, JA
通讯作者：
Gossen, JA
影响因子：
4.8
作者：
Litvin, TN;Kamenetsky, M;Levin, LR
通讯作者：
Levin, LR
影响因子：
3.6
作者：
Balbach, Melanie;Fushimi, Makoto;Buck, Jochen
通讯作者：
Buck, Jochen
影响因子：
4
作者：
Balbach, Melanie;Ghanem, Lubna;Levin, Lonny R.
通讯作者：
Levin, Lonny R.
影响因子：
14.8
作者：
Bradshaw JM;McFarland JM;Paavilainen VO;Bisconte A;Tam D;Phan VT;Romanov S;Finkle D;Shu J;Patel V;Ton T;Li X;Loughhead DG;Nunn PA;Karr DE;Gerritsen ME;Funk JO;Owens TD;Verner E;Brameld KA;Hill RJ;Goldstein DM;Taunton J
通讯作者：
Taunton J