James Francis Callahan

The use of γ-turn mimetics to define peptide secondary structure

Abstract A novel γ-turn mimetic 2 has been prepared based on retro amide peptide design. Incorporation of this mimetic into linear peptide fibrinogen receptor antagonist 7 (GPIIb/IIIa receptor) affords the opportunity to test models of antagonist pharmacophore.

Macrocycles in the construction of acyclic stereochemistry

Abstract The conformations of macrocyclic intermediates provide a useful medium through which distant chiral centers may control chemical reactions. In this paper, we show that macrocycles made by cyclization of simple acyclic starting materials with an auxiliary spacer may be used to prepare stereochemically complex acyclic products.

Antagonists of the calcium receptor I. Amino alcohol-based parathyroid hormone secretagogues.

Functional screening of the former SmithKline Beecham compound collection against the human calcium receptor (CaR) resulted in the identification of the amino alcohol-based hit 2 (IC(50) = 11 microM). Structure-activity studies of 2 focused on the optimization of the right- and left-hand side aromatic moieties as well as the amino alcohol linker region. Critical to the optimization of this antagonist template was the discovery that the chirality of the C-2 secondary alcohol played a key role in enhancing both CaR potency as well as selectivity over the beta-adrenergic receptor subtypes. These SAR studies ultimately led to the identification of 38 (NPS 2143; SB-262470A), a potent and orally active CaR antagonist. Pharmacokinetic characterization of 38 in the rat revealed that this molecule had a large volume of distribution (11 L/kg), which resulted in a prolonged systemic exposure, protracted increases in the plasma levels of PTH, and an overall lack of net bone formation effect in a rodent model of osteoporosis.

Benzimidazole derivatives as arginine mimetics in 1,4-benzodiazepine nonpeptide vitronectin receptor (αvβ3) antagonists

In a 3-oxo-1,4-benzodiazepine-2-acetic acid series of vitronectin receptor (αvβ3) antagonists containing a benzimidazole as a novel arginine mimetic, we examined the effects of benzimidazole modifications and amide substitutions on both activity and pharmacokinetics.

Structure-activity relationships in 3-oxo-1,4-benzodiazepine-2-acetic acid GPIIb/IIIa antagonists. The 2-benzazepine series

Abstract In an investigation of the contribution of N-1 to the binding, antiaggregatory, and oral activity in 3-oxo-1,4-benzodiazepine-2-acetic acid based GPIIb/IIIa antagonists, a series of 2-benzazepine analogs, wherein N-1 of the 1,4-benzodiazepine nucleus has been replaced by a methylene group, was examined.

Novel peptidomimetic hematoregulatory compounds

The activity of a novel series of peptidomimetic hematoregulatory compounds, designed based on a pharmacophore model inferred from the structure activity relationships of a peptide SK&F 107647 (1), is reported. These compounds induce a hematopoietic synergistic factor (HSF) which in turn modulates host defense. The compounds may represent novel therapeutic agents in the area of hematoregulation.

Peptide Mimetics as Adhesion Molecule Antagonists

As a class, drugs that modulate cell adhesion as a mechanism of action are in their infancy. Although several drugs are in clinical development as intravenous agents, none have reached the market. Even in this early period, however, the pursuit of adhesion molecule antagonists that may be administered orally has begun within the arena of platelet fibrinogen receptor antagonists (also called GPIIb/IIIa antagonists). As one of the more mature areas of antiadhesion, platelet fibrinogen receptor antagonists have advanced from the native protein fibrinogen to small potent inhibitory peptides, and more recently to potent semipeptide and nonpeptide antagonists. Although nonpeptide ligands to GPIIb/IIIa have been discovered through compound data-base screening, the path to non Peptides through peptide mimetics is also being avidly pursued. This chapter will focus on the development of an RGD peptide pharmacophore model for the design of novel nonpeptide mimetic ligands to GPIIb/IIIa. It will be instructive, however, to examine first the path that led to the discovery of small potent inhibitory peptide GPIIb/IIIa antagonists, focusing on the work at SmithKline Beecham.

Correction: Differential regulation of innate immune cytokine production through pharmacological activation of Nuclear Factor-Erythroid-2-Related Factor 2 (NRF2) in burn patient immune cells and monocytes (PLoS ONE (2017) 12:9 (e0184164) DOI: 10.1371/journal.pone.0184164)

[This corrects the article DOI: 10.1371/journal.pone.0184164.].

Conformational study of eight-membered diazocine turn mimics by two-dimensional NMR spectroscopy

The eight‐membered ring conformations of two diazocine turn mimics, methyl‐[2,5‐dioxo‐3‐(S)‐(3‐ω‐tosyl‐guanidino‐propyl)‐4‐methyl‐octahydro‐1,4‐diazocin‐1‐yl]acetate (I) and methyl‐[2,5‐dioxo‐3‐(S)‐(3‐ω‐tosyl‐guanidino‐propyl)‐octahydro‐1,4‐diazocin‐1‐yl]acetate (II), were determined using torsion angle constraints derived from 3J(C,H) coupling constants extracted from 13C‐filtered TOCSY spectra with 13C in natural abundance. For I, the torsion angle constraints derived from 3J(C,H) coupling constants were in agreement with torsion angle constraints derived from 3J(H,H) coupling constants extracted from a P.E.COSY spectrum. Similar 3J(C,H) coupling constants were found for I and II, and they shared an identical eight‐membered ring conformation characterized by two cis‐amide bonds and a staggered conformation of the trimethylene group in which the H3 proton is proximal to both the H6 and H8 protons.