Inge M. Michel

BMS-187257, a potent, selective, and novel heterocyclic β3 adrenergic receptor agonist

Abstract Novel heterocyclic β 3 adrenergic receptor agonists 2 were prepared and evaluated for their ability to bind to human β 1 , β 2 , and β 3 adrenergic receptors. Stimulatory effects on the β 3 adrenergic receptor were also measured. BMS-187257 ( 4b ) was found to be a potent and selective β 3 agonist.

α-hydroxy- and α-ketoester functionalized thrombin inhibitors

Abstract α-Hydroxy- and α-ketoester functionalized D-Phe-Pro-Lys tripeptides were found to be potent thrombin active site inhibitors. The ketoester derivatives were characterized by slow binding kinetics. The most potent of the series was 9 (BMS 181, 412) with an overall inhibition constant Ki* of 0.0017 μM.

Carboxyl-promoted enhancement of selectivity for the β3 adrenergic receptor. Negative charge of the sulfonic acid BMS-187413 introduces-β3 binding selectivity

Abstract Carboxyl and other negatively charged groups were found to be most effective at producing human β3 adrenergic receptor binding selectivity in 1 (BRL 37344) and related compounds. The sulfonic acid analog 7 (BMS-187413) is a novel and potent β3 adrenergic agonist that binds selectively, and thus has an in vitro profile that compares favorably with that of BRL 37344.

Binding and signal transduction of the cloned vascular angiotensin II (AT1a) receptor cDNA stably expressed in Chinese hamster ovary cells

The vascular angiotensin (A) II receptor cDNA (AT1a) was transfected into Chinese hamster ovary (CHO) cells to generate the stable cell line CHO-AT1a. This cell line was used to investigate the binding and signal transduction properties of the cloned vascular AT1 receptor. Specific binding of sarcosine1(-)[125I]tyrosine4-isoleucine8-AII ([125I]SI-AII) to CHO-AT1a membranes reached equilibrium after 1 h at 25 degrees C and was consistently greater than 95% of total binding. Saturation binding analyses demonstrated [125I]SI-AII bound to a saturable population of sites on membranes with an equilibrium dissociation constant (KD) of 0.7 nM and a binding site maximum of 1.2 pmol/mg protein. [125I]SI-AII binding to CHO cells was inhibited by the following compounds with a rank order of potency of SI-AII > AII > losartan > AI >> PD 123,177. AII (1 microM) treatment of CHO-AT1a cells caused an increase in inositol phosphates and intracellular calcium relative to basal levels. These responses were blocked by losartan but not by PD 123,177. AII (1 microM) did not effect adenylate cyclase activity in CHO-AT1a cells, whereas the agonist inhibited adenylate cyclase activity in rat liver cell membranes. These effects were blocked by 10 microM losartan. These results indicate that CHO-AT1a cells express functional AT1a receptors which stimulate phospholipase C activity but not adenylate cyclase activity. CHO-AT1a cells should provide a useful model for studies of AT1a receptor domains which are critical to signaling pathways.

Synthesis of pyrrolidine oxazoles as thromboxane A2/endoperoxide receptor antagonists

Abstract The synthesis and antiplatelet activity of a series of bis-heterocyclic thromboxane A2 receptor antagonists is described. The L-proline analog 9 was the most potent ligand in this class with a KD = 7.9±0.71 nM in washed human platelets.

Interphenylene 7-oxabicyclo[2.2.1]heptanes. SQ33,961: a new potent, long-acting thromboxane antagonist ☆

Abstract The synthesis and initial biological evaluation of a novel series of chiral interphenylene 7-oxabicyclo-[2.2.1]heptane TxA2 antagonists with 4-amido oxazole omega chains is described. Within this series SQ 33,961 has been identified as a highly potent TxA2 antagonist with an exceptionally long in vivo duration of action.

Thoromboxane A2/endoperoxide receptor antagonists: 1,3-Dioxane and 1,3-dioxolane analogs

Synthesis and in vitro pharmacological profile of several 1,3-dioxane and 1,3-dioxolane analogs are described. Compounds 1c and 1f are the two most potent thromboxane receptor antagonists with Kd values of 8.0± 0.4 nM and 8.2 ±0.4 nM, respectively at the TxA2PGH2 receptor in human platelet membrane.

Syntheses of Cyclopentane, Cyclohexene and Olefin Oxazoles as Thromboxane A2/Endoperoxide Receptor Antagonists

Abstract Synthesis and antiplatelet activity of a series of structurally simple thromboxane A 2 receptor antagonists are described. The cis -cyclopentane analog (−)- 1c was the most potent compound in this series with I 50 and K d values of 15 nM and 4.3 ±0.0 nM, respectively. In radioligant binding assay, trans -cyclopentane analog (−)- 1d was the most potent ligand with a K d value of 0.5±0.3 nM.

Interphenylene phenyl oxazoles: novel, potent thromboxane receptor antagonists

Abstract The synthesis and in vitro evaluation of a novel series of structurally simple interphenylene phenyl oxazoles 2 is described. The optimal interphenylene substitution pattern and carboxyl side chain length were determined and from this series 2b (SQ 34,942) was identified as a potent TxA2 antagonist (AAIPA I50=31 nM, Kd=19 nM).