Orally bioavailable amine-linked macrocyclic inhibitors of factor XIa |
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| Affiliation: | 1. Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26‑1, Muraoka‑Higashi 2‑chome, Fujisawa, Kanagawa 251‑8555, Japan;2. Takeda California, Inc., 10410 Science Center Drive, San Diego, CA 92121, United States;1. LSPCMIB, UMR-CNRS 5068, Université Paul Sabatier-Toulouse III, 118 Route de Narbonne, 31062 Toulouse Cedex 9, France;2. Institut de Chimie de Toulouse, FR2599, 118 Route de Narbonne, 31062 Toulouse, France;3. Dipartimento di Biologia e Biotecnologie “Lazzaro Spallanzani”, Via Ferrata 9, 27100 Pavia, Italy;1. Centre for Genetics and Inherited Diseases, Taibah University, Al-Madinah Al-Munawwarah, Kingdom of Saudi Arabia;2. Department of Chemistry, Allama Iqbal Open University, Islamabad 44000, Pakistan;3. Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea;4. Medicinal Chemistry & Pharmacology, Korea University of Science and Technology, Daejeon, South Korea;1. Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA;2. Discovery Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA;3. In vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA;4. Immunology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA;5. Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA;1. Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;2. Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA;1. Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China;2. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China;3. College of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China |
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| Abstract: | The discovery of orally bioavailable FXIa inhibitors has been a challenge. Herein, we describe our efforts to address this challenge by optimization of our imidazole-based macrocyclic series. Our optimization strategy focused on modifications to the P2 prime, macrocyclic amide linker, and the imidazole scaffold. Replacing the amide of the macrocyclic linker with amide isosteres led to the discovery of substituted amine linkers which not only maintained FXIa binding affinity but also improved oral exposure in rats. Combining the optimized macrocyclic amine linker with a pyridine scaffold afforded compounds 23 and 24 that were orally bioavailable, single-digit nanomolar FXIa inhibitors with excellent selectivity against relevant blood coagulation enzymes. |
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| Keywords: | Factor Xia FXIa Activated partial thromboplastin time aPTT Thrombosis |
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