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The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.

This contribution reports the effects of molecular recognition events and solubility on the crystallization of carbamazepine (CBZ) polymorphs from organic solvents. Solvents were chosen on the basis of their hydrogen-bonding potential. Experiments were conducted to (1) measure solubilities and induction times, (2) monitor solution concentrations and solid phase compositions, and (3) identify intermolecular interactions between solvents and CBZ molecules. Primitive monoclinic, CBZ(M), and trigonal, CBZ(Trg), carbamazepine anhydrous polymorphs readily crystallized from the organic solvents. CBZ(Trg) is the metastable form at 25 °C with a solubility approximately 1.2 times that of CBZ(M). Results show that relative nucleation rates of CBZ polymorphs are dependent on the hydrogen-bonding nature of the solvent and are not dependent on solubility. Solvents that primarily accept hydrogen bonds (donor-to-acceptor ratio (d/a) ) 0) preferentially crystallized CBZ(Trg), whereas solvents that accept and donate hydrogen bonds (d/a > 0.5) concomitantly crystallized CBZ(M) and CBZ(Trg). Evaluation of the crystal structures shows that specific interactions between acceptor solvents and the CBZ dimer led to the prevention of the molecular motif necessary for CBZ(M) nucleation. It is concluded that intermolecular interactions and specifically the hydrogen-bonding propensity of solvents with CBZ molecules have profound effects on the molecular self-assembly and selective crystallization of CBZ polymorphs.

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Angioscopic plaque rupture and thrombus were independently associated with adverse outcome in patients with complex lesions after interventional procedures. These features were not identified by either angiography or intravascular ultrasound.