Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design.
Katherine L LeeCatherine M AmblerDavid R AndersonBrian P BoscoeAndrea G BreeJoanne I BrodfuehrerJeanne S ChangChulho ChoiSeungwon ChungKevin J CurranJacqueline E DayChristoph M DehnhardtKen DowerSusan E DrozdaRichard K FrisbieLori K GavrinJoel A GoldbergSeungil HanMartin HegenDavid HepworthHeidi R HopeSatwik KamtekarIain C KiltyArthur LeeLih-Ling LinFrank E LoveringMichael D LoweJohn P MathiasHeidi M MorganElizabeth A MurphyNikolaos PapaioannouAkshay PatnyBetsy S PierceVikram R RaoEddine SaiahIvan J SamardjievBrian M SamasMarina W H ShenJulia H ShinHolly H SoutterJoseph W StrohbachPeter T SymanowiczJennifer R ThomasonJohn D TrzupekRichard VargasFabien VincentJiangli YanChristoph W ZapfStephen W WrightPublished in: Journal of medicinal chemistry (2017)
Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.