Fragment-based identification and optimization of a class of potent pyrrolo[2,1-f][1,2,4]triazine MAP4K4 inhibitors |
| |
| Institution: | 1. Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States;2. Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States;3. Department of Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States;4. Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States;5. Department of Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States;1. Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main St., Cambridge, MA 02139, United States;2. Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Eastern Point Rd., Groton, CT 06340, United States;3. Primary Pharmacology Group, Pfizer Worldwide R&D, Eastern Point Rd., Groton, CT 06340, United States;4. Neuroscience Research Unit, Pfizer Worldwide R&D, 610 Main St., Cambridge, MA 02139, United States;5. Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D, 610 Main St., Cambridge, MA 02139, United States;6. Drug Safety R&D, Pfizer Worldwide R&D, Eastern Point Rd., Groton, CT 06340, United States;1. Novel Drug Design and Discovery Laboratory, Department of Pharmaceutical Chemistry, S.E.T''s College of Pharmacy, Sangolli Rayanna Nagar, Dharwad 580 002, India;2. Centre for Research and Development, Prist University, Thanjavur, Tamil Nadu 613 403, India;3. BDR Pharmaceuticals International Pvt. Ltd, Baroda, Gujarat, India;4. Université de Toulouse, UPS, Laboratoire de Synthèse et Physico-Chimie de Molécules d''Intérêt Biologique, LSPCMIB, 118 Route de Narbonne, F-31062 Toulouse Cedex 9, France;1. Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA;2. Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;3. British Heart Foundation Centre of Research Excellence, Imperial College London, Sir Alexander Fleming Building, Room 258, London W12 ONN, UK;1. Pfizer Worldwide Research and Development, 200 Cambridge Park Drive, Cambridge, MA 02140, United States;2. Pfizer Worldwide Research and Development, 1 Eastern Point Road, Groton, CT 06340, United States;3. Pfizer Worldwide Research and Development, 10777 Science Center Drive, San Diego, CA 92121, United States |
| |
| Abstract: | MAP4K4 has been shown to regulate key cellular processes that are tied to disease pathogenesis. In an effort to generate small molecule MAP4K4 inhibitors, a fragment-based screen was carried out and a pyrrolotriazine fragment with excellent ligand efficiency was identified. Further modification of this fragment guided by X-ray crystal structures and molecular modeling led to the discovery of a series of promising compounds with good structural diversity and physicochemical properties. These compounds exhibited single digit nanomolar potency and compounds 35 and 44 achieved good in vivo exposure. |
| |
| Keywords: | MAP4K4 Fragment-based lead discovery Pyrrolotriazine Kinase inhibitors P-loop conformation |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
