2. Academic Validation
  3. A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors

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

  • J Med Chem. 2021 Nov 25;64(22):16770-16800. 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
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486 United States.
  • 2 Department of Discovery Pharmaceutical Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States.
  • 3 Department of Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486 United States.
  • 4 Peptides and Small Molecule Research and Development Department, IRBM S.p.A., Via Pontina km 30600, 00071 Pomezia (RM), Italy.
  • 5 Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486 United States.
  • 6 Department of Modeling and Informatics, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States.
  • 7 Department of Discovery Biology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States.
  • 8 Department of Medicinal Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States.
  • 9 Department of Process Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States.
  • 10 Department of Structural Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033 United States.
PMID: 34704436 DOI: 10.1021/acs.jmedchem.1c01599
Abstract

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.

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