| Institution: | 1. Department of Medicinal Chemistry, Argenta, 8/9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom;2. Department of Computer Aided Drug Design, Argenta, 8/9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom;3. Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States;4. Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States;5. Department of Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States;6. Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States;7. Department of Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States |
| Abstract: | The identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which display nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan-JAK inhibitor (tofacitinib). |
