Amination of Nitro-Substituted Heteroarenes by Nucleophilic Substitution of Hydrogen.

An open-air method for the transition metal-free direct amination of nitro(hetero)arenes by anilines is disclosed. In this methodology, an aromatic C-H bond is substituted via oxidative nucleophilic aromatic substitution of hydrogen (ONSH). Density functional theory calculations and mechanistic studies support a dianion pathway with oxidation by molecular oxygen as the rate-limiting step.

Overcoming Limitations in Decarboxylative Arylation via Ag-Ni Electrocatalysis.

A useful protocol for achieving decarboxylative cross-coupling (DCC) of redox-active esters (RAE, isolated or generated in situ) and halo(hetero)arenes is reported. This pragmatically focused study employs a unique Ag-Ni electrocatalytic platform to overcome numerous limitations that have plagued this strategically powerful transformation. In its optimized form, coupling partners can be combined in a surprisingly simple way: open to the air, using technical-grade solvents, an inexpensive ligand and Ni source, and substoichiometric AgNO3, proceeding at room temperature with a simple commercial potentiostat. Most importantly, all of the results are placed into context by benchmarking with state-of-the-art methods. Applications are presented that simplify synthesis and rapidly enable access to challenging chemical space. Finally, adaptation to multiple scale regimes, ranging from parallel milligram-based synthesis to decagram recirculating flow is presented.

Structural and Thermal Characterization of Halogenated Azidopyridines: Under-Reported Synthons for Medicinal Chemistry.

Owing to their participation in Click reactions, bifunctional azides are valuable intermediates in the preparation of medicines and biochemical tool compounds. Despite the privileged nature of pyridines among pharmaceutical scaffolds, reports of the synthesis and characterization of azidopyridines bearing a halogen substituent for further elaboration are almost completely unknown in the literature. As azidopyridines carry nearly equal numbers of nitrogen and carbon atoms, we hypothesized that safety concerns limited the application of these useful bifunctional building blocks in medicinal and biological chemistry. To address this concern, we prepared and characterized nine azidopyridines bearing a single fluorine, chlorine, or bromine atom. All were examined by differential scanning calorimetry (DSC), in which they demonstrated exotherms of 228-326 kJ/mol and onset temperatures between 119 and 135 °C. Selected azidopyridines were advanced to mechanical stress testing, in which impact sensitivity was noted for one regioisomer of C5H3FN4. The utility of these versatile intermediates was demonstrated through their use in a variety of Click reactions and the diversification of the halogen handles.

Discovery of Milvexian, a High-Affinity, Orally Bioavailable Inhibitor of Factor XIa in Clinical Studies for Antithrombotic Therapy.

Factor XIa (FXIa) is an enzyme in the coagulation cascade thought to amplify thrombin generation but has a limited role in hemostasis. From preclinical models and human genetics, an inhibitor of FXIa has the potential to be an antithrombotic agent with superior efficacy and safety. Reversible and irreversible inhibitors of FXIa have demonstrated excellent antithrombotic efficacy without increased bleeding time in animal models (Weitz, J. I., Chan, N. C. Arterioscler. Thromb. Vasc. Biol. 2019, 39 (1), 7-12). Herein, we report the discovery of a novel series of macrocyclic FXIa inhibitors containing a pyrazole P2' moiety. Optimization of the series for (pharmacokinetic) PK properties, free fraction, and solubility resulted in the identification of milvexian (BMS-986177/JNJ-70033093, 17, FXIa Ki = 0.11 nM) as a clinical candidate for the prevention and treatment of thromboembolic disorders, suitable for oral administration.

Azatricyclic Inverse Agonists of RORγt That Demonstrate Efficacy in Models of Rheumatoid Arthritis and Psoriasis.

Structure-activity relationship studies directed toward the replacement of the fused phenyl ring of the lead hexahydrobenzoindole RORγt inverse agonist series represented by 1 with heterocyclic moieties led to the identification of three novel aza analogs 5-7. The hexahydropyrrolo[3,2-f]quinoline series 5 (X = N, Y = Z=CH) showed potency and metabolic stability comparable to series 1 but with improved in vitro membrane permeability and serum free fraction. This structural modification was applied to the hexahydrocyclopentanaphthalene series 3, culminating in the discovery of 8e as a potent and selective RORγt inverse agonist with an excellent in vitro profile, good pharmacokinetic properties, and biologic-like in vivo efficacy in preclinical models of rheumatoid arthritis and psoriasis.

Reductions in log P improved protein binding and clearance predictions enabling the prospective design of cannabinoid receptor (CB1) antagonists with desired pharmacokinetic properties.

Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile.

Characterization of a novel and selective CB1 antagonist as a radioligand for receptor occupancy studies.

Obesity remains a significant public health issue leading to Type II diabetes and cardiovascular disease. CB1 antagonists have been shown to suppress appetite and reduce body weight in animal models as well as in humans. Evaluation of pre-clinical CB1 antagonists to establish relationships between in vitro affinity and in vivo efficacy parameters are enhanced by ex vivo receptor occupancy data. Synthesis and biological evaluation of a novel and highly selective radiolabeled CB1 antagonist is described. The radioligand was used to conduct ex vivo receptor occupancy studies.

Discovery of pyrazine carboxamide CB1 antagonists: the introduction of a hydroxyl group improves the pharmaceutical properties and in vivo efficacy of the series.

Structure-activity relationships for a series of pyrazine carboxamide CB1 antagonists are reported. Pharmaceutical properties of the series are improved via inclusion of hydroxyl-containing sidechains. This structural modification sufficiently improved ADME properties of an orally inactive series such that food intake reduction was achieved in rat feeding models. Compound 35 elicits a 46% reduction in food intake in ad libidum fed rats 4-h post-dose.

Potent and selective biphenyl azole inhibitors of adipocyte fatty acid binding protein (aFABP).

Herein we report the first disclosure of biphenyl azoles that are nanomolar binders of adipocyte fatty acid binding protein (aFABP or aP2) with up to thousand-fold selectivity against muscle fatty acid binding protein and epidermal fatty acid binding protein. In addition a new radio-ligand to determine binding against the three fatty acid binding proteins was also synthesized.

Reduction of site-specific CYP3A-mediated metabolism for dual angiotensin and endothelin receptor antagonists in various in vitro systems and in cynomolgus monkeys.

2-{Butyryl-[2'-(4,5-dimethyl-isoxazol-3-ylsulfamoyl)-biphenyl-4-ylmethyl]-amino}-N-isopropyl-3-methyl-butyramide (BMS-1) is a potent dual acting angiotensin-1 and endothelin-A receptor antagonist. The compound was subject to rapid metabolic clearance in monkey and human liver microsomes and exhibited low systemic exposure and marked interanimal variability in cynomolgus monkeys after p.o. administration. The variability pattern was identical to that of midazolam given p.o. in the same monkeys, as measured by area under the curve and Cmax values, suggesting that CYP3A-mediated metabolism might play a role in the rapid clearance and observed interanimal variability. Subsequent in vitro metabolism studies using human liver microsomes and cDNA-expressed human cytochrome P450 (P450) enzymes revealed that BMS-1 was a CYP3A4 substrate and was not metabolized by other human P450 enzymes. Mass spectral and NMR analyses of key metabolites led to the identification of the dimethyl isoxazole group as a major metabolic soft spot for BMS-1. Replacement of the 4-methyl group on the isoxazole ring with halogens not only improved overall metabolic stability but also decreased CYP3A-mediated hydroxylation of the isoxazole 5-methyl group. As exemplified by 2-{butyryl-[2'-(4-fluoro-5-methyl-isoxazol-3-ylsulfamoyl)-biphenyl-4-ylmethyl]-amino}-N-isopropyl-3-methyl-butyramide (BMS-3), a fluorinated analog of BMS-1, the structural modification resulted in an increase in the systemic exposure relative to previous analogs and a dramatic reduction in interanimal variability in the monkeys after p.o. administration. In addition, BMS-3 could be metabolized by both CYP2C9 and CYP3A4, thus avoiding the reliance on a single P450 enzyme for metabolic clearance. Integration of results obtained from in vitro metabolism studies and in vivo pharmacokinetic evaluations enabled the modulation of site-specific CYP3A-mediated metabolism, yielding analogs with improved overall metabolic profiles.