No abstract

A series of inhibitors of angiotensin converting enzyme (ACE, dipeptidyl carboxypeptidase, EC 3.4.15.1) is described which addresses certain conformational aspects of the enzyme-inhibitor interaction. In this study the alanylproline portion of the potent ACE inhibitor enalaprilat (2) is replaced by a series of monocyclic lactams containing the required recognition and binding elements. In order to more fully assess the lactam ring conformations and the key backbone angle psi as defined in 3 with respect to possible enzyme-bound conformations, a series of model lactams was investigated with use of molecular mechanics. The results point to a correlation between inhibitor potency (IC50) and the computed psi angle for the lowest energy conformation of the model compounds. Thus the psi angle as defined in 3 is an important determinant in the binding of inhibitors to ACE. The inhibition data in conjunction with the computational data have served to define a window of psi angles from 130 degrees to 170 degrees which seems to be acceptable to the ACE active site.

Adamantyl triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). They are active both in in vitro and in in vivo pharmacodynamic models. The synthesis and structure-activity relationships of these inhibitors are presented.

Nuclear receptor activation is dependent on recruitment of coactivators, including CREB-binding protein (CBP/p300) and steroid receptor coactivator-1 (SRC-1).A three-dimensional NMR approach was used to probe the coactivator binding interface in the peroxisome proliferator-activated receptor ␥ (PPAR␥) ligand binding domain (LBD). In the presence of a CBP peptide, peaks corresponding to 20 residues in helices 3, 4, 5, and 12 of the LBD were attenuated. Alanine mutants revealed that K301A, V315A, Y320A, L468A, and E471A were required for binding of both CBP and SRC-1 and for cellbased transcription. Several additional amino acids in helix 4 of the PPAR␥LBD were defective with respect to CBP recruitment, but retained relatively normal SRC-1 recruitment. Thus these amino acid residues may be important determinants of specificity for nuclear receptor LBD interactions with discrete coactivator molecules.Nuclear receptors are a large family of ligand-activated transcription factors that control important cell functions. Nuclear receptors contain a central DNA binding domain and a COOHterminal ligand binding domain (LBD) 1 with an activation function domain (AF2). Ligand-induced transactivation is mediated through interactions with members of a growing family of coactivator proteins, such as CBP (1-4), SRC-1 (3, 5-9), PGC-1(10), PBP (11, 12), TRAP220 (13), and ARA70 (14). A short sequence motif LXXLL which is shared by most coactivators has been shown to be required to mediate the ligandinduced receptor-coactivator interaction through AF2 (15)(16)(17). Mechanisms that confer the specificity for the nuclear receptorcoactivator interaction have become a central focus of investigation in this field. Different nuclear receptors have been found to preferentially interact with different coactivators and corepressors (18), suggesting that interactions besides LXXLL-AF2 binding per se play important roles. Darimont et al. (16) and McInerney et al. (17) have shown that the amino acids immediately adjacent the LXXLL motifs impart specific binding to selected nuclear receptors. Here, we identified the LBD residues of PPAR␥ that are required for both CBP and SRC-1 binding; in addition, we also identified several amino acids that differentially affect binding to CBP and SRC-1. These results suggest that certain residues within the LBD of nuclear receptors have an important role in mediating functional specificity by allowing for differential interactions with individual coactivators.

We report new SSTR5 antagonists with enhanced potency, subtype selectivity, and minimal off-target activities as compared to previously reported compounds. Starting from the reported SSTR5 antagonist 1, we systematically surveyed changes in the central core and head piece while maintaining the diphenyl tail group constant. From this study the azaspirodecanone 10 emerged as a new highly potent and selective SSTR5 antagonist. Compound 10 lowered glucose excursion by 94% in an oral glucose tolerance test (OGTT) in mice following a 3 mg/kg oral dose. The compound increased both total and active circulating incretin hormone GLP-1 levels in mice at a dose of 10 mg/kg. A synergistic effect was also demonstrated when compound 10 was coadministered with a DPP-4 inhibitor, substantially increasing circulating active GLP-1[7−36] amide and insulin in response to a glucose challenge.