William C. Ripka

A short and stereospecific synthesis of (±)-α-lycorane

Abstract (±)-α-Lycorane (4) has been synthesized stereospecifically in five steps from commercially available 3,4-(methylenedioxy)phenylacetonitrile (7). The key step involves an intramolecular unstabilized iminium ylide-olefin [3+2] cyclo addition reaction 6 → 9.

Design and synthesis of a novel class of thrombin inhibitors incorporating heterocyclic dipeptide surrogates

Abstract Several potent and selective inhibitors of thrombin incorporating novel heterocyclic peptide surrogates in the P3-P2 position of peptidyl argininals have been discovered. Illustrated in this article are three classes of heterocycles: pyridones, uracils, and pyrimidinones. The synthesis and biological activities of these unique aromatic heterocyclic derivatives are reported herein.

Rational design, synthesis, and serine protease inhibitory activity of a novel P1-argininal derivative featuring a conformationally constrained P2–P3 bicyclic lactam moiety

Abstract Based on molecular modeling and judicious combination of the salient topographic features of the recently discovered P3-lactam derivative 1 with the P2-prolyl derivatives 2a, b, the novel thrombin inhibitor 3a was designed. Inhibitor 3a incorporates a fused bicyclic lactam as a novel type of P2–P3 dipeptide surrogate. The synthesis and biological activity of this potent serine protease inhibitor is presented.

Synthesis and biological activity of P2–P4 azapeptidomimetic P1-argininal and P1-ketoargininamide derivatives: a novel class of serine protease inhibitors

Abstract Molecular modeling and topographic considerations of the thrombin-specific sequences Boc-Asp-Pro-Arg-TS or Ac-d-Phe-Pro-Arg-TS (TS = transition state analog electrophilic center) and related scaffolds led to the design of novel P 2 –P 4 -azapeptidomimetic P 1 -argininal and P 1 -ketoargininamide derivatives ( 3a-j ). The synthesis and biological activity of these potential serine protease inhibitors are presented.

Novel and general method for the preparation of peptidyl argininals

Abstract A general method for the synthesis of peptidyl argininals was developed which utilizes the novel building block N g -nitro-L-argininal ethyl aminal·HCl. The final aldehyde structure is generated by hydrolysis of the peptidic aminal moiety and can be applied to highly functionalized peptidic structures. The method is amenable to the preparation of large quantities of enantiomerically pure peptidyl argininals and was applied to the synthesis of two potent thrombin inhibitors.

Rational design and synthesis of a novel, selective class of thrombin inhibitors: P1-argininal derivatives incorporating P3P4 quaternary lactam dipeptide surrogates

Abstract SAR and molecular modeling investigations on the potent and selective thrombin inhibitor 1b (CVS 1578) and related serine protease inhibitors led to the design of series 2a–g, featuring quaternary α-amino-α-benzyl-lactam scaffolds that serve as novel P3P4 dipeptide mimics. The design, synthesis, and biological activity of these targets are presented.

Novel Synthesis of Potent Site-Specific Phospholipase A2 Inhibitors

Phospholipase A2 (PLA2) is an esterase responsible for the liberation of phospholipid-bound arachidonic acid, a biosynthetic precursor of putative inflammatory mediators. Arachidonic acid is metabolized by cyclooxygenase and lipoxygenase to the corresponding prostaglandins and leukotrienes (Fig. 1). Traditional antiinflammatory therapy has relied on cyclooxygenase and more recently on lipoxygenase blockade (Shen, 1981), but direct control of arachidonic acid pools has remained relatively unexplored. Recent evidence (Hirata et al., 1980; Blackwell et al., 1980; Rothhut et al., 1983) demonstrates that antiinflammatory steroids control polyunsaturated fatty acid release at both cyclooxygense and lipoxygenase pathways by enhancing the production of PLA2 inhibitory proteins (lipomodulin, macrocortin, renocortin). Direct phospholipase A2 site-specific inhibition, therefore, offers new opportunities in antiinflammatory treatment.

RATIONAL DESIGN, SYNTHESIS, AND SERINE PROTEASE INHIBITORY ACTIVITY OF NOVEL P1-ARGININOYL HETEROCYCLES

Abstract Peptidomimetic derivatives featuring a P1-argininoyl heterocycle were designed. The preparation of two key building blocks containing benzoxazole or benzimidazole rings and their incorporation into thrombin and factor Xa specific sequences is described. The serine protease inhibitory activity of these targets was evaluated. Molecular modeling of two representative structures is presented.

Modeling rhodopsin, a member of G-protein coupled receptors, by computer graphics. Interpretation of chemical shifts of fluorinated rhodopsins

Abstract— An attempt has been made to construct a 3‐D model of rhodopsin, a member of G‐protein coupled receptors. Sequence homology of rhodopsin with the latter was a factor considered in the modeling procedure. The constructed model has been used to compare currently available specific protein/substrate interaction information, the shape of the binding cavity derived from shape of binding retinal isomers and analogs and challenged to explain recently available results from a series of fluorinated rhodopsins.

Using 3-D Similarity Searching to Develop Synthetic Targets

One of the key challenges facing the medicinal chemist is converting data obtained from X-ray crystallography, biological screening, and mechanism studies into ideas for new synthetic targets. To develop these new targets, two problems must be solved. First, a pharmacophore model representing the 3-D arrangement of the functional groups required for biological activity must be developed. Then, a molecular framework must be found which can position these functional groups in the proper 3-D orientation. This paper reviews our approaches to developing pharmacophore models and how these models can be used as input for searching 3-D databases to find desirable molecular ‘frameworks’. Our 3-D searching is done using the GEOSTAT software from the Cambridge Crystallographic Data Centre and Molecular Design Limited’s MACCS-3D software. Results for several pharmacophores will be used to illustrate how the technique can be used to develop novel synthetic targets.