The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated (
R)-3-amino-3-phenylpropionic acid series, ...the current compounds showed improved in vitro potency and metabolic stability. Compound
17, 2-((2
R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-
N-((1
R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide, showed EC
50 of 10.3
nM in a rabbit biochemical challenge model. The practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described.
Current sampling of genomic sequence data from eukaryotes is relatively poor, biased, and inadequate to address important questions about their biology, evolution, and ecology; this Community Page ...describes a resource of 700 transcriptomes from marine microbial eukaryotes to help understand their role in the world's oceans.
The therapeutic alliance has consistently predicted client outcomes in psychotherapy. This study uses attachment theory as a resource in understanding the therapeutic alliance. Participants in this ...study were 27 mothers, 15 fathers, and 23 adolescents that participated in family therapy. Results indicate that mothers' reports of trust in their oldest child predicted the alliance, and adolescent ratings of trust in mothers and fathers moderated the relationship between therapy alliance and symptom distress. Implications for family therapy research and practice are discussed.
The ribonuclease inhibitor protein (RI) binds to members of the bovine pancreatic ribonuclease (RNase A) superfamily with an affinity in the femtomolar range. Here, we report on structural and ...energetic aspects of the interaction between human RI (hRI) and human pancreatic ribonuclease (RNase 1). The structure of the crystalline hRI {center_dot} RNase 1 complex was determined at a resolution of 1.95 {angstrom}, revealing the formation of 19 intermolecular hydrogen bonds involving 13 residues of RNase 1. In contrast, only nine such hydrogen bonds are apparent in the structure of the complex between porcine RI and RNase A. hRI, which is anionic, also appears to use its horseshoe-shaped structure to engender long-range Coulombic interactions with RNase 1, which is cationic. In accordance with the structural data, the hRI {center_dot} RNase 1 complex was found to be extremely stable (t{sub 1/2} = 81 days; K{sub d} = 2.9 x 10{sup -16}). Site-directed mutagenesis experiments enabled the identification of two cationic residues in RNase 1, Arg39 and Arg91, that are especially important for both the formation and stability of the complex, and are thus termed 'electrostatic targeting residues'. Disturbing the electrostatic attraction between hRI and RNase 1 yielded a variant of RNase 1 that maintained ribonucleolytic activity and conformational stability but had a 2.8 x 10{sup 3}-fold lower association rate for complex formation and 5.9 x 10{sup 9}-fold lower affinity for hRI. This variant of RNase 1, which exhibits the largest decrease in RI affinity of any engineered ribonuclease, is also toxic to human erythroleukemia cells. Together, these results provide new insight into an unusual and important protein-protein interaction, and could expedite the development of human ribonucleases as chemotherapeutic agents.
We describe herein the design, synthesis, and antiviral activity of a series of P4 modified tetrapeptidyl α-ketoamides as HCV protease inhibitors. The most promising analog identified through this ...SAR,
5a,
5c, and
5e demonstrated excellent enzyme inhibitory potency, enzyme selectivity, cellular activity, and acceptable therapeutic indexes.
With the aim of improving HCV protease inhibitors reported in our previous manuscripts, we synthesized and evaluated a series of
1a-based tetrapeptidyl α-ketoamides with additional P4 modification. The promising analog discovered through this SAR,
5a, was further derivatized at P1′ or P1 position. As a result of these efforts, we found that replacement of the P4 valine as seen in
1a with cyclohexylglycine (Chg) resulted in the discovery of
5a,
5c, and
5e endowed with improved cellular activity in comparison to
1a.
The bradykinin B1 receptor is induced following tissue injury and/or inflammation. Antagonists of this receptor have been studied as promising candidates for treatment of chronic pain. We have ...identified aryl sulfonamides containing a chiral chroman diamine moiety that are potent antagonists of the human B1 receptor. Our previously communicated lead, compound 2, served as a proof-of-concept molecule, but suffered from poor pharmacokinetic properties. With guidance from metabolic profiling, we performed structure−activity relationship studies and have identified potent analogs of 2. Variation of the sulfonamide moiety revealed a preference for 3- and 3,4-disubstituted aryl sulfonamides, while bulky secondary and tertiary amines were preferred at the benzylic amine position for potency at the B1 receptor. Modifying the β-amino acid core of the molecule lead to the discovery of highly potent compounds with improved in vitro pharmacokinetic properties. The most potent analog at the human receptor, compound 38, was also active in a rabbit B1 receptor cellular assay. Furthermore, compound 38 displayed in vivo activity in two rabbit models, a pharmacodynamic model with a blood pressure readout and an efficacy model of inflammatory pain.
PDF
