John J. Acton

(±)-Trans-2-(3-methoxy-5-methylsulfonyl-4-propoxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (L-659,989), a novel, potent PAF receptor antagonist

The title compound, L-659,989, is a highly potent, competitive, and selective antagonist of the binding of [3H]PAF to its receptors in platelet membranes from rabbits and humans. It exhibits equilibrium inhibition constants for PAF binding of 1.1 nM (rabbit) to 9.0 nM (human), values that are at least 1-2 orders of magnitude lower than those of other PAF antagonists tested. L-659,989 potently inhibits PAF-induced aggregation of rabbit platelets and degranulation of rat (ED50 4.5 nM) and human (ED50 10 nM) neutrophils. L-659,989 inhibits PAF-induced extravasation and lysosomal enzyme release in rats, and is active orally in female rats (ED50 0.2 mg/kg) with an extraordinary oral duration of action of 12 to 16 hours at 1.0 mg/kg p.o.

Discovery of (2R)-2-(3-{3-[(4-Methoxyphenyl)carbonyl]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl}phenoxy)butanoic Acid (MK-0533): A Novel Selective Peroxisome Proliferator-Activated Receptor γ Modulator for the Treatment of Type 2 Diabetes Mellitus with a Reduced Potential to Increase Plasma and Extracellular Fluid Volume

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists are used to treat type 2 diabetes mellitus (T2DM). Widespread use of PPARgamma agonists has been prevented due to adverse effects including weight gain, edema, and increased risk of congestive heart failure. Selective PPARgamma modulators (SPPARgammaMs) have been identified that have antidiabetic efficacy and reduced toxicity in preclinical species. In comparison with PPARgamma full agonists, SPPARgammaM 6 (MK0533) displayed diminished maximal activity (partial agonism) in cell-based transcription activation assays and attenuated gene signatures in adipose tissue. Compound 6 exhibited comparable efficacy to rosiglitazone and pioglitazone in vivo. However, with regard to the induction of untoward events, 6 displayed no cardiac hypertrophy, attenuated increases in brown adipose tissue, minimal increases in plasma volume, and no increases in extracellular fluid volume in vivo. Further investigation of 6 is warranted to determine if the improvement in mechanism-based side effects observed in preclinical species will be recapitulated in humans.

Design of potent and selective GPR119 agonists for type II diabetes.

Screening of the Merck sample collection identified compound 1 as a weakly potent GPR119 agonist (hEC(50)=3600 nM). Dual termini optimization of 1 led to compound 36 having improved potency, selectivity, and formulation profile, however, modest physical properties (PP) hindered its utility. Design of a new core containing a cyclopropyl restriction yielded further PP improvements and when combined with the termini SAR optimizations yielded a potent and highly selective agonist suitable for further preclinical development (58).

Synthesis and biological activity of MK 287 (L-680,573): a potent, specific and orally active paf receptor antagonist

Abstract An enantioselective synthesis of MK 287 (L-680,573), a member of a family of trans-,5-diaryltetrahydrofurans, and its biological activity are described.

Synthesis and derivatization of a versatile α-substituted lactam dipeptide isostere

Abstract The diastereoselective synthesis of a versatile lactam constrained dipeptide isostere is described. The facile derivatization of this intermediate is demonstrated.

Tetrapeptide derived inhibitors of complexation of a class II MHC: the peptide backbone is not inviolate.

Major histocompatabilty (MHC) proteins rely heavily on peptide backbone recognition for ligation. Nonetheless, modifications to the polyamide backbone of a tetrapeptide ligand can be made without abrogating binding.

Selectivity in the dehydration of 15-membered azalides

Dehydration at the 6-hydroxy group of two isomeric 15-membered azalides shows opposing regioselectivity. Azithromycin (1) favours the E-Δ6,7-isomer while L-701677 (8) generates the Δ6,18-isomer.