Theoretical Study of Structures and Ring-Puckering Potential Energy Functions of Bicylo[3.1.0]hexane and Related Molecules

Ab initio computations using the MP2/cc-pVTZ method have been carried out to calculate the structures and relative energies of the different conformations of five bicyclic molecules including bicyclo[3.1.0]­hexane, 3-oxabicyclo[3.1.0]­hexane, 6-oxabicyclo[3.1.0]­hexane, 3,6-oxabicyclo[3.1.0]­hexane, and bicyclo[3.1.0]­hexan-3-one. Theoretical ring-puckering potential energy functions (PEFs) in terms of the ring-puckering coordinate have been calculated for each of the molecules and these were compared to those determined experimentally from spectroscopic data. Each potential function is asymmetric and has an energy minimum corresponding to where the five-membered ring is puckered in the same direction as the attached three-membered ring. In contrast to the experimental result, the calculations predict that bicyclo[3.1.0]­hexane has a second shallow energy minimum. All of the other molecules have a single conformational minimum and their experimental and theoretical PEFs agree very well. The wave functions for the lower ring-puckering energy levels have been computed

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>

Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

The discovery of BMS-605339 (<b>35</b>), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropyl­acylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1′ site of the protease. The identification of <b>35</b> was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound <b>35</b> which demonstrated antiviral activity in HCV-infected patients

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>)