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Finding small non-peptide molecules for G protein-coupled receptors (GPCR) whose endogenous ligands are peptides, is a very important task for medicinal chemists. Over the years, compounds mimicking peptide structures have been discovered, and scaffolds emulating peptide backbones have been designed. In our work on GPCR ligands, including cholecystokinin receptor-1 (CCKR-1) agonists, we have employed benzodiazepines as a core structure. Looking for ways to reduce molecular weight and possibly improve physical properties of GPCR ligands, we embarked on the search for molecules providing similar scaffolds to the benzodiazepine with lower molecular weight. One of our target core structures was 1,4-dihydro-[1,4]diazepine-5,7-dione. There was not, however, a known synthetic route to such molecules. Here we report the discovery of a simple and concise method for synthesis of 2-[6-(1H-indazol-3-ylmethyl)-5,7-dioxo-4-phenyl-4,5,6,7-tetrahydro-[1,4]diazepin-1-yl]-N-isopropyl-N-phenyl-acetamide as an example of a compound containing the tetrahydrodiazepine-5,7-dione core. Compounds from this series were tested in numerous GPCR assays and demonstrated activity at melanocortin 1 and 4 receptors (MC1R and MC4R). Selected compounds from this series were tested in vivo in Peptide YY (PYY)-induced food intake. Compounds dosed by intracerebroventricular and oral routes reduced PYY-induced food intake and this effect was reversed by the cyclic peptide MC4R antagonist SHU9119.

A novel class of pyrrolidinyl-acetyleneic thieno[3,2-d]pyrimidines has been identified which potently inhibit the EGFR and ErbB-2 receptor tyrosine kinases. Synthetic modifications of the pyrrolidine carbamate moiety result in a range of effects on enzyme and cellular potency. In addition, the impact of the absolute stereochemical configuration on cellular potency and oral mouse pharmacokinetics is described.

A series of dianilinopyrimidineureas demonstrate potency as VEGFR2 kinase inhibitors.

The dihydroxylation of olefins using AD-mix or OsO 4 K 3 Fe(CN) 6 in the presence of sulfides has been examined as has the rate of oxidation of various classes of sulfides. The selectivity of olefin oxidation in preference to sulfur oxidation depends on the nature of the sulfur moiety, and can be problematic for certain classes of substrates.

Aniline ‘headgroups’ were synthesized and incorporated into an alkynyl thienopyrimidine series of EGFR and ErbB-2 inhibitors. Potent inhibition of enzyme activity and cellular proliferation was observed. In certain instances, protein binding was reduced and oral exposure was found to be somewhat improved relative to compounds containing the reference aniline.

A novel series of P1 modified HIV protease inhibitors was synthesized and evaluated for in vitro antiviral activity against wild-type virus and protease inhibitor-resistant viruses. Optimization of the P1 moiety resulted in compounds with femtomolar enzyme activities and cellular antiviral activities in the low nanomolar range culminating in the identification of clinical candidate GW0385.

A series of novel N-alkoxy-arylsulfonamide HIV protease inhibitors with low picomolar enzyme activity and single digit nanomolar antiviral activity is disclosed.

Rotational depletion coherence spectroscopy permits the determination of ground-state rotational constants of photodissociable ions from orientation recurrences observed for the remaining ions after substantial depletion by a linearly polarized ps pulse of light at wavelengths absorbed by the ions. The method is complementary to ordinary rotational coherence spectroscopy. It has been tested on the 40 Ar + 3 and 36 Ar + 3 ions, whose rotational constants are (9.0±0.2)×10 8 s −1 and (10.0±0.2)× 8 s −1 , respectively.