Christopher Franklin Bigge

Discovery of a Series of Imidazo[4,5-b]pyridines with Dual Activity at Angiotensin II Type 1 Receptor and Peroxisome Proliferator-Activated Receptor-gamma.

Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-γ (PPARγ) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPARγ confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPARγ activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC(50) = 1.6 nM) with partial PPARγ agonism (EC(50) = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.

AMPA receptor agonists, antagonists and modulators: their potential for clinical utility

Ligands with four pharmacologically distinct actions at the AMPA receptor are discussed. The four classes of compounds include agonists, antagonists, positive allosteric modulators, and negative allosteric modulators of AMPA receptor function. To date, no partial agonists have been discovered. Agonists and positive allosteric modulators may have therapeutic potential in disease states where hypoactivity of glutamatergic tone exists. From our understanding of neuronal circuitry and its involvement in brain function, agonists and positive allosteric modulators are predicted to improve the negative symptomatology in schizophrenia, and to improve memory, behavioural and cognition skills in dementias associated with neurodegenerative disorders or trauma. Issues related to the structural overlap of competitive AMPA receptor antagonists and NMDA glycine site (GlyN) antagonists are addressed; emphasis is directed toward AMPA antagonist activity. Competitive antagonists and negative allosteric modulators (non-comp...

VISUAL PIGMENTS AND BACTERIORHODOPSINS FORMED FROM AROMATIC RETINAL ANALOGS

Abstract— Rhodopsin (Rh) and bacteriorhodopsin (bR) analogs have been prepared from retinals containing various aromatic and heterocyclic nuclei. In the case of Rh, aromatic methyl substituents facilitate the regeneration and stabilize the pigments formed; in bR, however, methyl substituents seem to have little influence. Rhodopsins derived from unsubstituted aromatic retinals show fine structure in the relatively stable “pre‐pigment” intermediate and their maxima are red‐shifted compared to pigments derived from methylated aromatic retinals. This implies that in these aromatic rhodopsins the ring moiety adopts a more planar conformation when unsubstituted. In bR derivatives also the aromatic ring adopts a close‐to‐planar conformation when unsubstituted, but comparison with indene‐derived bR suggests that even the unsubstituted phenyl ring may not be coplanar with the side‐chain.

Conversion of uracil nucleotides into isotopically labelled 5-substituted uracil nucleotides: a convenient route to thymine nucleotides

Unprotected uracil nucleotides and nucleosides are converted into 5-formyluracil derivatives using a palladium(II) coupling reaction followed by oxidation of the intermediate styryl derivative.