Aberrant signaling of phosphoinositide 3-kinase δ (PI3Kδ) has been implicated in numerous pathologies including hematological malignancies and rheumatoid arthritis. Described in this manuscript are the discovery, optimization, and in vivo evaluation of a novel series of pyridine-containing PI3Kδ inhibitors. This work led to the discovery of 35, a highly selective inhibitor of PI3Kδ which displays an excellent pharmacokinetic profile and is efficacious in a rodent model of rheumatoid arthritis.
Acalabrutinib is a targeted, covalent inhibitor of Bruton tyrosine kinase (BTK) with a unique 2-butynamide warhead that has relatively lower reactivity than other marketed acrylamide covalent inhibitors. A human [ 14 C] microtracer bioavailability study in healthy subjects revealed moderate intravenous clearance (39.4 l/h) and an absolute bioavailability of 25.3% 6 14.3% (n = 8). Absorption and elimination of acalabrutinib after a 100 mg [ 14 C] microtracer acalabrutinib oral dose was rapid, with the maximum concentration reached in <1 hour and elimination half-life values of <2 hours. Low concentrations of radioactivity persisted longer in the blood cell fraction and a peripheral blood mononuclear cell subfraction (enriched in target BTK) relative to plasma. [ 14 C]Acalabrutinib was metabolized to more than three dozen metabolites detectable by liquid chromatography-tandem mass spectrometry, with primary metabolism by CYP3A-mediated oxidation of the pyrrolidine ring, thiol conjugation of the butynamide warhead, and amide hydrolysis. A major active, circulating, pyrrolidine ring-opened metabolite, ACP-5862 (4-[8-amino-3-[4-(but-2-ynoylamino)butanoyl]imidazo[1,5-a]pyrazin-1yl]-N-(2-pyridyl)benzamide), was produced by CYP3A oxidation. Novel enol thioethers from the 2-butynamide warhead arose from glutathione and/or cysteine Michael additions and were subject to hydrolysis to a b-ketoamide. Total radioactivity recovery was 95.7% 6 4.6% (n = 6), with 12.0% of dose in urine and 83.5% in feces. Excretion and metabolism characteristics were generally similar in rats and dogs. Acalabrutinib's highly selective, covalent mechanism of action, coupled with rapid absorption and elimination, enables high and sustained BTK target occupancy after twice-daily administration.
Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) is an appealing target for several hematological malignancies and inflammatory diseases. Herein, we describe the discovery and optimization of a series of propeller shaped PI3Kδ inhibitors comprising a novel triaminopyrimidine hinge binder. Combinations of electronic and structural strategies were employed to mitigate aldehyde oxidase mediated metabolism. This medicinal chemistry effort culminated in the identification of 52, a potent and highly selective inhibitor of PI3Kδ that demonstrates efficacy in a rat model of arthritis.
Polymer-bound allyl sulfones (cf. 9) were utilized in geminal cycloalkylations with epichlorohydrin
to generate a cis-phenylsulfonylcyclobutanol derivative (cf. 11) in one step. In the final step of this
solid-phase synthetic sequence, cuprate, organomolybdenum, and organopalladium reagents were
screened to obtain an optimal protocol for “traceless” cleavage of cyclobutylidene products from
the resin. Among these, palladium-catalyzed allylic alkylation was the most efficient. In addition,
highly regioselective nucleophilic attack at the less hindered terminus of the allyl fragment (i.e.,
overall SN2‘ sulfinate displacement) was observed. Cyclobutylidene diversification was demonstrated
by incorporating different allylic substituents, O-functionalizations, and C-nucleophiles to prepare
a demonstration library of eight cyclobutylidene derivatives (i.e., derivatives of 4) in four steps
and 30−38% overall yield from lithium polystyrene/divinylbenzene sulfinate.
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