Asymmetric Synthesis of the Major Metabolite of a Calcitonin Gene-Related Peptide Receptor Antagonist and Mechanism of Epoxide Hydrogenolysis

An asymmetric synthesis of the major metabolite of the calcitonin gene-related peptide recepotor antagonist BMS-846372 is presented. The variously substituted cyclohepta­[<i>b</i>]­pyridine ring system represents an underexplored ring system and showed some unexpected chemistry. Reactivities of epoxide and ketone functional groups on the cycloheptane ring were extensively controlled by a remote bulky TIPS group. The rate difference of the hydrogenolysis between two diastereomeric epoxide intermediates shed some light on the mechanism of epoxide hydrogenolysis, and further, deuterium labeling studies revealed more mechanistic details on this well-known chemical transformation for the first time

Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents

By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine <b>18</b> with 34-fold improved BACE1 inhibitory activity over the lead compound <b>1</b>. The cocrystal structure of <b>18</b> 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 <b>26</b> as a very potent BACE1 inhibitor (IC₅₀ < 1 nM). This compound demonstrated robust brain Aβ reduction in rat dose–response studies. Thus, compound <b>26</b> may be useful in testing the amyloid hypothesis of Alzheimer’s disease

Potent Inhibitors of Hepatitis C Virus NS3 Protease: Employment of a Difluoromethyl Group as a Hydrogen-Bond Donor

The design and synthesis of potent, tripeptidic acylsulfonamide inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl amino acid at P1 are described. A cocrystal structure of <b>18</b> with a NS3/4A protease complex suggests the presence of a H-bond between the polarized C–H of the CHF₂ moiety and the backbone carbonyl of Leu135 of the enzyme. Structure–activity relationship studies indicate that this H-bond enhances enzyme inhibitory potency by 13- and 17-fold compared to the CH₃ and CF₃ analogues, respectively, providing insight into the deployment of this unique amino acid

Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies

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 <b>4</b>, the known benzofuran analogue <b>5</b>, and the benzothiadiazine derivative <b>6</b>, an optimization process utilizing the simple benzofuran template <b>7</b> 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 (<b>37</b>), 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 <b>37</b> were better than anticipated and suggest promising potential for QD administration

Discovery and Preclinical Characterization of the Cyclopropylindolobenzazepine BMS-791325, A Potent Allosteric Inhibitor of the Hepatitis C Virus NS5B Polymerase

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 (<b>2</b>) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation

Design and Synthesis of 4‑Heteroaryl 1,2,3,4-Tetrahydroisoquinolines as Triple Reuptake Inhibitors

A series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) was discovered. The synthesis and structure–activity relationship (SAR) of these triple reuptake inhibitors (TRIs) will be discussed. Compound <b>10i</b> (AMR-2), a very potent inhibitor of SERT, NET, and DAT, showed efficacy in the rat forced-swim and mouse tail suspension models with minimum effective doses of 0.3 and 1 mg/kg (<i>po</i>), respectively. At efficacious doses in these assays, <b>10i</b> exhibited substantial occupancy levels at the three transporters in both rat and mouse brain. The study of the metabolism of <b>10i</b> revealed the formation of a significant active metabolite, compound <b>13</b>

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 <i>N</i>-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 (<b>6</b>) and its active parent molecule BMS-986169 (<b>5</b>), which demonstrated high binding affinity for the GluN2B allosteric site (<i>K</i>_i = 4.0 nM) and selective inhibition of GluN2B receptor function (IC₅₀ = 24 nM) in cells. The conversion of prodrug <b>6</b> to parent <b>5</b> was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds <b>5</b> and <b>6</b> 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 <b>5</b>, <b>6</b>, or the major circulating metabolites <b>met-1</b> and <b>met-2</b>. The prodrug BMS-986163 (<b>6</b>) has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder

Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing

The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (<b>2</b>) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to <b>2</b>, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like <b>2</b>, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (<b>1</b>) from clinical trials. Structure–activity relationships (SARs) at each of the structural subsites in <b>2</b> were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (<b>29</b>)