Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.
The determination of the relative stability of multipolymorph compounds is very important to chemical processes and product development. Two thermodynamic methods are used in this study: a eutectic method and a pure component method. The eutectic method, requiring suitable additives to form eutectic mixtures, 1 was reported by L. Yu in 2005. The pure component method is newly developed by the authors. This method involves two innovative approaches. First, thermodynamic equations are derived for the Gibbs free energy difference between a pair of polymorphs, based upon a pathway from one polymorph, through a supercooled liquid, to another polymorph. Second, HyperDSC is used for the accurate measurement of heat capacity and melting data for each polymorph at a high heating rate to avoid form conversion/recrystallization between polymorphs and potential product decomposition. A polymorphic system consisting of five polymorphs is used for demonstrating these two methods. The Gibbs free energy difference between polymorphs with respect to the reference polymorph calculated from the novel pure component method is comparable with that from the eutectic method. The locations of the crossover temperatures from these two methods are in very good agreement with results from the experimental competitive slurrying experiments.
The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (37), which maintained ligand efficiency relative to early leads, demonstrated efficacy in a triple combination regimen in HCV replicon cells, and exhibited consistently high oral bioavailability and pharmacokinetic parameters across preclinical animal species. The human PK properties from the Phase I clinical studies of 37 were better than anticipated and suggest promising potential for QD administration.
By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC 50 < 1 nM). This compound demonstrated robust brain Aβ reduction in rat dose−response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer's disease.
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