Edward C. Lawson

Nonpeptide Urotensin-II Receptor Antagonists: A New Ligand Class Based on Piperazino-Phthalimide and Piperazino-Isoindolinone Subunits

We have discovered two related chemical series of nonpeptide urotensin-II (U-II) receptor antagonists based on piperazino-phthalimide (5 and 6) and piperazino-isoindolinone (7) scaffolds. These structure types are distinctive from those of U-II receptor antagonist series reported in the literature. Antagonist 7a exhibited single-digit nanomolar potency in rat and human cell-based functional assays, as well as strong binding to the human U-II receptor. In advanced pharmacological testing, 7a blocked the effects of U-II in vitro in a rat aortic ring assay and in vivo in a rat ear-flush model. A discussion of U-II receptor antagonist pharmacophores is presented, and a specifically defined model is suggested from tricycle 13, which has a high degree of conformational constraint.

1,2,4-Triazolo[3,4-a]pyridine as a novel, constrained template for fibrinogen receptor (GPIIb/IIIa) antagonists

Conformationally constrained analogues of the GPIIb/IIIa antagonist elarofiban (RWJ-53308) have been synthesized and biologically evaluated. The 1,2,4-triazolo[3,4-a]pyridine scaffold provided potent antagonists with favorable pharmacodynamic and pharmacokinetic attributes in dogs. Compounds 12a and 13a exhibited enhancements in oral bioavailability, t(1/2), and ex vivo duration of action (inhibition of ADP-induced platelet aggregation) relative to elarofiban.

Synthesis of triazolopyridines as conformationally constrained tertiary amides

Amide derivatives of cyclic amines are common templates for biologically active chemical entities. To constrain the tertiary amide moiety of N-acylpiperidine-based GPIIb/IIIa antagonists for further structureˇactivity study, we have prepared new 1,2,4-triazolo[4,3-a]pyridines. The syntheses of two classes of triazolopyridines are reported. # 2000 Elsevier Science Ltd. All rights reserved.

REMOTE STEREOCONTROL IN ACYCLIC SYSTEMS. HYDRIDE ADDITION TO 1,5- AND 1,6-HYDROXY KETONES MEDIATED BY METAL CHELATION

Acyclic 1,6-hydroxy amino ketones can be reduced to either the anti or syn diols with high 1,6 diastereoselectivity by sequential treatment with a Lewis acid and a borohydride reagent, with the direction of stereocontrol depending on the Lewis acid complexant used. For example, with 1a anti:syn ratios of >100:1 [Ti(OiPr)4/K-Selectride] and 1:7 [Al(OEt)3/K-Selectride] were realized. 1,5-Hydroxy amino ketone 4a was reduced with high syn 1,5 diastereoselectivity [anti:syn = 1:18 with Al(OEt)3/K-Selectride].