Corinne E. Augelli-Szafran

Potent bicyclic lactam inhibitors of thrombin: Part I: P3 modifications.

Peptidomimetic inhibitors of general structure 1 have been prepared. Optimization of the binding affinities of these compounds through variation of the P3 hydrophobic residue is described. Selected substituted bicylic lactams displayed interesting pharmacological profiles both in vitro and in vivo.

Chapter 3. β-Amyloid as a Target for Alzheimer's Disease Therapy

Publisher Summary This chapter analyzes β-amyloid as a target for Alzheimers disease (AD) therapy. One of the cardinal pathological signatures of AD is the deposition of the β-amyloid (Aβ) peptide in the cores of senile plaques and in the walls of cerebral blood vessels. This 39-42 amino acid peptide is formed from the cleavage of a larger species, the β-amyloid precursor protein (βAPP), and is prone to self-aggregation. The Aβ peptide plays a key role in the pathogenesis of AD. One approach for blocking the formation of β-amyloid is to inhibit the polymerization of this peptide. For other amyloidoses, such as AA and AL amyloidosis, it has been shown that blocking or removing the amyloidogenic peptide, can reverse the process. This chapter discusses the search for amyloid fibrillization inhibitors. Use of techniques, such as electron microscopy, X-ray diffraction, atomic force microscopy (AFM), light scattering, fluorescence, nuclear magnetic resonance (NMR), and Fourier-transform infrared spectroscopy (FTIR) for analysis of amyloids is discussed. An overview of β-amyloid inhibitors is presented and inhibition of Aβ toxicity is also discussed in the chapter.

Cholecystokinin B antagonists. Synthesis and quantitative structure-activity relationships of a series of C-terminal analogues of CI-988☆

A study of structure-activity relationships of a series of dipeptoid CCK-B receptor antagonists was performed in which variations of the phenyl ring were examined while the [(2-adamantyloxy)carbonyl]-alpha-methyl-R)-tryptophan moiety of the potent antagonist CI-988 was kept constant. Since the main focus of this study was phenyl substituent variation, series design techniques were employed to insure an adequate spread of physicochemical properties (lipophilic, steric, electronic), as well as positional substitution. A QSAR analysis on sets of 26 and 16 analogues revealed that CCK-B affinity was related to a combination of the overall size and, marginally, lipophilicity of the phenyl ring substituents (i.e., smaller groups were associated with increased potency with an optimum pi near zero, respectively). Further exploration revealed that the dimensions and electronics of the para-phenyl substituent could be related to CCK-B affinity. Increased affinity was seen with short, bulky (branched) electron withdrawing groups. Analogs with small para-substituents appeared to be about 1000-fold CCK-B selective, indicating that selectivity for CCK-B binding is sensitive to phenyl ring substitution. The 4-F-phenyl dipeptoid, derived from this study, has extraordinary high affinity at the CCK-B receptor (IC50 = 0.08 nM) and was also very selective (940-fold CCK-B selective). Consistent with previous reports, (S)-configuration at the substituted phenethylamide center, a carboxylic acid and the presence of a phenyl ring were found to be associated with increased affinity at both CCK-A and CCK-B receptors.

Z-(±)-1-azabicyclo[2.2.1]heptan-3-one, O-(3-aryl-2-propynyl) oximes as potential m1-subtype selective muscarinic agonists

Abstract The synthesis and SAR of a series of Z-(±)-1-azabicyclo[2.2.1]heptan-3-one, O-(3-aryl-2-propynyl) oximes are described. The biochemistry and pharmacology of PD 142505 (5b), an oxime with pronounced functional ml selectivity, are highlighted.

SAR study of the indole moiety of CI-988, a potent and selective CCK-B antagonist

Abstract Due to the interesting pharmacological activity observed for CI-988, a potent and selective CCK-B receptor antagonist, we have continued to study the SAR of this antagonist. This particular study examines the importance of the indole moiety for binding affinity. The synthesis and receptor binding affinity for analogs containing functionalized indole derivatives and replacing the indole with various heterocycles are reported.

Identification and characterization of m1 selective muscarinic antagonists

Our interest in the area of m4 muscarinic antagonists had led us to study a series of benzoxazine isoquinolines. One of the most potent and selective compounds of this series is example 1 with an IC50 value of 90.7 nM at m4 receptors, and 72-fold (m1), 38-fold (m2), 10-fold (m3), and 82-fold (m5) more selective compared to the other receptors. The synthesis and receptor binding affinity of analogs of 1 are reported.