دورية أكاديمية
A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors.
| العنوان: | A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors. |
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| المؤلفون: | Tucker TJ; Department of Medicinal Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486 United States., Embrey MW; Department of Medicinal Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486 United States., Alleyne C; Department of Discovery Pharmaceutical Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States., Amin RP; Department of Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486 United States., Bass A; Department of Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486 United States., Bhatt B; Department of Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486 United States., Bianchi E; Peptides and Small Molecule Research and Development Department, IRBM S.p.A., Via Pontina km 30600, 00071 Pomezia (RM), Italy., Branca D; Peptides and Small Molecule Research and Development Department, IRBM S.p.A., Via Pontina km 30600, 00071 Pomezia (RM), Italy., Bueters T; Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486 United States., Buist N; Department of Discovery Pharmaceutical Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States., Ha SN; Department of Modeling and Informatics, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States., Hafey M; Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486 United States., He H; Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486 United States., Higgins J; Department of Discovery Pharmaceutical Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States., Johns DG; Department of Discovery Biology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States., Kerekes AD; Department of Medicinal Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States., Koeplinger KA; Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486 United States., Kuethe JT; Department of Process Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States., Li N; Department of Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486 United States., Murphy B; Department of Discovery Biology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States., Orth P; Department of Structural Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States., Salowe S; Department of Discovery Biology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States., Shahripour A; Department of Medicinal Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States., Tracy R; Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486 United States., Wang W; Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486 United States., Wu C; Department of Medicinal Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486 United States., Xiong Y; Department of Medicinal Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States., Zokian HJ; Department of Discovery Biology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States., Wood HB; Department of Medicinal Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States., Walji A; Department of Medicinal Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2021 Nov 25; Vol. 64 (22), pp. 16770-16800. Date of Electronic Publication: 2021 Oct 27. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| مواضيع طبية MeSH: | PCSK9 Inhibitors/*pharmacology , Peptides, Cyclic/*pharmacology, Administration, Oral ; Animals ; Biological Availability ; Crystallography, X-Ray ; Macaca fascicularis ; Molecular Structure ; PCSK9 Inhibitors/chemistry ; PCSK9 Inhibitors/pharmacokinetics ; Peptides, Cyclic/chemistry ; Peptides, Cyclic/pharmacokinetics ; Rats ; Structure-Activity Relationship |
| مستخلص: | 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. |
| المشرفين على المادة: | 0 (PCSK9 Inhibitors) 0 (Peptides, Cyclic) |
| تواريخ الأحداث: | Date Created: 20211027 Date Completed: 20220128 Latest Revision: 20220128 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1021/acs.jmedchem.1c01599 |
| PMID: | 34704436 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.1c01599 |