2-Aminothiophene derivatives as a new class of positive allosteric modulators of glucagon-like peptide 1 receptor.

We report the discovery of two new 2-aminothiophene based small molecule positive allosteric modulators (PAMs) of glucagon-like peptide 1 receptor (GLP-1R) for the treatment of type 2 diabetes. One of the chemotypes, (S-1), has a molecular weight of 239 g/mol, the smallest molecule among all reported GLP-1R PAMs. When combined with GLP-1 peptide, S-1 increased the GLP-1R activity in a dose-dependent manner in a cell-based assay. When combined with the peptide agonist of vasoactive intestinal polypeptide receptor 1 (VIPR1), S-1 showed no specific activity on VIPR1, another class B GPCR present in the same HEK293-CREB cell line. Insulin secretion studies found S-1 combined with GLP-1 increased insulin secretion by 1.5-fold at 5 µM. In a mechanistic study, evidence is provided that the synergistic effect of S-1 with GLP-1 may be partly due to the enhanced impact on CREB based phosphorylation. Given the favorable profile of these chemotypes, the work reported herein suggests that 2-aminothiophene derivatives are a new and promising class of GLP-1R PAMs.

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 (35), 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 35 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 35 which demonstrated antiviral activity in HCV-infected patients.

Influence of intraoperative fluid volume on cardiopulmonary bypass hematocrit and blood transfusions in coronary artery bypass surgery.

A hematocrit (Hct) of less than 25% during cardiopulmonary bypass (CPB) and transfusion of homologous packed red blood cells (PRBC) are each associated with an increased probability of adverse events in cardiac surgery. Although the CPB circuit is a major contributor to hemodilution intravenous (IV) fluid volume may also significantly influence the level of hemodilution. The objective of this study was to explore the influence of asanguinous IV fluid volume on CPB Hct and intraoperative PRBC transfusion. After Institutional Review Board approval, a retrospective chart review of 90 adult patients that had undergone an elective, isolated CABG with CPB was conducted. Regression analysis was used to determine if pre-CPB fluid volume was associated with the lowest CPB Hct and the incidence of an intraoperative PRBC transfusion. In separate multivariate analyses, higher pre-CPB fluid volume was associated with lower minimum CPB Hct (p < .0001), and higher minimum CPB Hct was associated with a decreased probability of PRBC transfusion (p < .0001). Compared to patients that received <1600 mL (n = 55) of pre-CPB fluid, those that received >1600 mL (n = 35) had a decreased mean low CPB Hct (22.4% vs 25.6%, p < .0001), an increased incidence of a CPB Hct <25% (74% vs. 38%, p = .0008) and PRBC transfusion (60% vs. 16%, p < .0001), and increased median PRBC units transfused (2.0 vs 1.0, p = .1446) despite no significant difference in gender, age, patient size, baseline Hct, or CPB prime volume. Patients that received a PRBC transfusion (n = 30) received a significantly higher volume of pre-CPB fluid than nontransfused patients (1800 vs. 1350 mL, p = .0039). These findings suggest that pre-CPB fluid volume can significantly contribute to hemodilutional anemia in cardiac surgery. Optimizing pre-CPB volume may preserve baseline Hct and help limit intraoperative hemodilution.

PTC124 targets genetic disorders caused by nonsense mutations.

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.

Rational design of 6-methylsulfonylindoles as selective cyclooxygenase-2 inhibitors.

The introduction of 3-arylmethyl, 3-aryloxy and 3-arylthio moieties into a 6-methylsulfonylindole framework using rational drug design led to potent, selective COX-2 inhibitors having efficacy in a rat carrageenan air pouch model. Incorporation of a conformationally more rigid 3-aroyloxy substituent onto the 6-methylsulfonylindole scaffold led to selective, but considerably less potent COX-2 inhibitors. Variation of the hydrophilicity and size of the indole 2-substituent of 3-arylthio-6-methylsulfonylindole inhibitors led to modulation of the COX-2 human whole blood (HWB) potency and selectivity.

Chirospecific Syntheses of Conformationally Constrained 7-Azabicycloheptane Amino Acids by Transannular Alkylation.

A new method is reported for the chirospecific preparation of optically pure 1-carboxy-7-azabicycloheptane amino acids for the generation of peptidomimetics as conformational probes. The method allows for the multigram preparation of these amino acid analogues through use of a thiolactam sulfide contraction and a transannular alkylation sequence as the key C-C bond-forming steps, starting from L-glutamic acid. The route provides access to two common intermediates, 7-(benzyloxycarbonyl)-1-carboxy-7-azabicyclo[2.2.1]-3-heptane and (1S,4R)-7-(benzyloxycarbonyl)-1-carboxy-7-azabicyclo[2.2.1]-3-heptanone tert-butyl ester, for elaboration to symmetrical and chiral amino acid homologues, respectively. Decarboxylation of the C-1 carboxy unit of the latter intermediate also demonstrated the applicability of the method for a short, chirospecific preparation of a (+)-epibatidine intermediate, (1S,4R)-7-(tert-butyloxycarbonyl)-1-carboxy-7-azabicyclo[2.2.1]-3-heptanone.