Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates,Journal of Medicinal Chemistry

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Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-11-08 , DOI: 10.1021/acs.jmedchem.2c01133
Michael Miller ₁ , Thomas Rossetti ₂ , Jacob Ferreira ₂ , Lubna Ghanem ₂ , Melanie Balbach ₂ , Navpreet Kaur ₂ , Lonny R Levin ₂ , Jochen Buck ₂ , Maria Kehr ₃ , Sandrine Coquille ₃ , Joop van den Heuvel ₄ , Clemens Steegborn ₃ , Makoto Fushimi ₁ , Efrat Finkin-Groner ₁ , Robert W Myers ₁ , Stacia Kargman ₁ , Nigel J Liverton ₁ , David J Huggins _{1,

5} , Peter T Meinke _{1,

2}

Affiliation

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.

中文翻译：

第二代慢解离速率可溶性腺苷酸环化酶 (sAC, ADCY10) 抑制剂的设计、合成和药理学评价

可溶性腺苷酸环化酶 (sAC: ADCY10) 是一种参与细胞内信号传导的酶。 sAC 的抑制在许多领域具有潜在的治疗用途。例如，sAC 对于男性成功生育至关重要：sAC 激活是精子活力和进行顶体反应的能力所必需的，这两个过程是卵母细胞受精的核心过程。对现有 sAC 抑制剂作为按需非激素男性避孕药的药理学评估表明，高内在效力、快速作用和缓慢解离速率是成功男性避孕药应用的基本设计要素。在此描述的药物化学活动过程中，我们确定了满足这些标准并适合多种 sAC 药理学的体内评估的 sAC 抑制剂。

更新日期：2022-11-08

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