A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors,Journal of Medicinal Chemistry

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A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-27 , DOI: 10.1021/acs.jmedchem.1c01599
Thomas J Tucker ₁ , Mark W Embrey ₁ , Candice Alleyne ₂ , Rupesh P Amin ₃ , Alan Bass ₃ , Bhavana Bhatt ₃ , Elisabetta Bianchi ₄ , Danila Branca ₄ , Tjerk Bueters ₅ , Nicole Buist ₂ , Sookhee N Ha ₆ , Mike Hafey ₅ , Huaibing He ₅ , John Higgins ₂ , Douglas G Johns ₇ , Angela D Kerekes ₈ , Kenneth A Koeplinger ₅ , Jeffrey T Kuethe ₉ , Nianyu Li ₃ , BethAnn Murphy ₇ , Peter Orth ₁₀ , Scott Salowe ₇ , Aurash Shahripour ₈ , Rodger Tracy ₅ , Weixun Wang ₅ , Chengwei Wu ₁ , Yusheng Xiong ₈ , Hratch J Zokian ₇ , Harold B Wood ₈ , Abbas Walji ₈

Affiliation

Department of Medicinal Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486 United States.
Department of Discovery Pharmaceutical Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States.
Department of Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486 United States.
Peptides and Small Molecule Research and Development Department, IRBM S.p.A., Via Pontina km 30600, 00071 Pomezia (RM), Italy.
Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486 United States.
Department of Modeling and Informatics, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States.
Department of Discovery Biology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States.
Department of Medicinal Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States.
Department of Process Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States.
Department of Structural Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States.

Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. Starting from second-generation lead structures such as 2, we were able to refine these structures to obtain extremely potent bi- and tricyclic PCSK9 inhibitor peptides. Optimized molecules such as 44 demonstrated sufficient oral bioavailability to maintain therapeutic levels in rats and cynomolgus monkeys after dosing with an enabled formulation. We demonstrated target engagement and LDL lowering in cynomolgus monkeys essentially identical to those observed with the clinically approved, parenterally dosed antibodies. These molecules represent the first report of highly potent and orally bioavailable macrocyclic peptide PCSK9 inhibitors with overall profiles favorable for potential development as once-daily oral lipid-lowering agents. In this manuscript, we detail the design criteria and multiparameter optimization of this novel series of PCSK9 inhibitors.

中文翻译：

一系列新型、高效和口服生物可利用的下一代三环肽 PCSK9 抑制剂

前蛋白转化酶枯草杆菌蛋白酶样/kexin 9 型 (PCSK9) 是血浆低密度脂蛋白胆固醇 (LDL-C) 的关键调节剂，是治疗高胆固醇血症和冠状动脉疾病的临床验证靶点。从第二代先导结构如2开始，我们能够改进这些结构以获得极强的双环和三环 PCSK9 抑制肽。44等优化分子在使用启用的制剂给药后，证明了足够的口服生物利用度以维持大鼠和食蟹猴的治疗水平。我们在食蟹猴中证明了靶标参与和 LDL 降低与临床批准的肠胃外给药抗体观察到的基本相同。这些分子代表了高效和口服生物可利用的大环肽 PCSK9 抑制剂的第一份报告，其总体特征有利于作为每日一次口服降脂剂的潜在开发。在这份手稿中，我们详细介绍了这一新型 PCSK9 抑制剂系列的设计标准和多参数优化。

更新日期：2021-11-25

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