Discovery of BMS-986339, a Pharmacologically Differentiated Farnesoid X Receptor Agonist for the Treatment of Nonalcoholic Steatohepatitis.

While several farnesoid X receptor (FXR) agonists under clinical investigation for the treatment of nonalcoholic steatohepatitis (NASH) have shown beneficial effects, adverse effects such as pruritus and elevation of plasma lipids have limited their clinical efficacy and approvability. Herein, we report the discovery and preclinical evaluation of compound 32 (BMS-986339), a nonbile acid FXR agonist with a pharmacologically distinct profile relative to our previously reported agonist BMS-986318. Compound 32 exhibited potent in vitro and in vivo activation of FXR, albeit with a context-dependent profile that resulted in tissue-selective effects in vivo. To our knowledge, this is the first report that demonstrates differential induction of Fgf15 in the liver and ileum by FXR agonists in vivo. Compound 32 demonstrated robust antifibrotic efficacy despite reduced activation of certain genes in the liver, suggesting that the additional pharmacology of BMS-986318 does not further benefit efficacy, possibly presenting an opportunity for reduced adverse effects. Further evaluation in humans is warranted to validate this hypothesis.

Co2(CO)8 as a Solid CO (g) Source for the Amino Carbonylation of (Hetero)aryl Halides with Highly Deactivated (Hetero)arylamines.

Carbonylation of (hetero)aryl iodides/bromides with highly deactivated 2-aminopyridines using Pd-Co(CO)4 bimetallic catalysis is accomplished. The use of Co2(CO)8 as a solid CO(g) source enhanced reaction rates observed when compared to CO(g), and excellent yields highlight the versatility of the developed protocol. A wide range of electronically and sterically demanding heterocyclic amines and (hetero)aryl iodides/bromides employed for this study resulted in excellent yields of amino carbonylated products. The developed methodology was further extended to synthesize Trypanosome brucie and luciferase inhibitors.

BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder.

There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N-methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 (6) and its active parent molecule BMS-986169 (5), which demonstrated high binding affinity for the GluN2B allosteric site (Ki = 4.0 nM) and selective inhibition of GluN2B receptor function (IC50 = 24 nM) in cells. The conversion of prodrug 6 to parent 5 was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds 5 and 6 have exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant off-target activity was observed for 5, 6, or the major circulating metabolites met-1 and met-2. The prodrug BMS-986163 (6) has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder.

Synthesis and antimicrobial evaluation of novel 4-amino-6-(1,3,4-oxadiazolo/1,3,4-thiadiazolo)-pyrimidine derivatives.

A series of novel 4-amino-6-(1,3,4-oxadiazolo/1,3,4-thiadiazolo)-pyrimidine derivatives of biological interest were prepared by sequential amination, hydrazide formation, and hydrazine carbothioamidination followed by cyclization. All the synthesized compounds (6a-6h and 7a-7f) were screened for antibacterial and antifungal activity. From this group, compound 7f (MIC (µg/mL µg/mL )/Inhibition (mm): 6.25/23-30) showed good antibacterial and antifungal activity. Reagents and conditions: (a) Ethyl acetoacetate, 60% NaH, 1,4-dioxane, 60°C, 6 h; (b) DIPEA, 1,4-dioxane, 100°C, 14 h; (c) NH2NH2 ⋅ H2O, EtOH, reflux, 14 h; (d) Tolyl isothiocyanatobenzene, DMF, RT, 2 h; (e) (if X = O) EDC⋅ HCl, TEA, DMF, RT, 14 h; (f) (if X = S) Conc. H2O4, RT, 14h.