effectively in cyclizations with N-acyliminum species. Electron-attracting substituents other than N-acyl, such as N-sulfonyl, can also be employed in analogues of N-acyliminium ion reactions. However, this review will concentrate on cyclizations of the N-acyl type, encompassing groups such as alkanoyl, aroyl, carbalkoxy, and N,N-dialkylcarbamyl, with limited coverage of sulfonyl groups. Most significantly, this review will focus on intramolecular reactions of N-acyliminium ions that result in the formation of new carbon-carbon bonds, rather than new carbonheteroatom bonds. Although β-lactam synthesis based on the cyclocondensation of imines with acid halides, Bruce E. Maryanoff earned B.S. (1969) and Ph.D. (1972) degrees from Drexel University and then conducted postdoctoral studies at Princeton University, working with Prof. Kurt Mislow. He joined McNeil Laboratories, a Johnson & Johnson subsidiary, in 1974 and advanced to Distinguished Research Fellow, the highest scientific position in the company. From 1976 to 1992, he principally worked on discovering drugs for treating central nervous system disorders; in 1992, he moved into cardiovascular research and presently leads the Vascular Research Team. Dr. Maryanoff is recognized for his work in organic and medicinal chemistry, especially the Wittig olefination reaction; peptides and peptidomimetics; antiepileptics and antidepressants; thrombin inhibitors; and protease-activated receptors. He discovered TOPAMAX topiramate, which is marketed worldwide for the treatment of epilepsy and is being developed for migraine headache. He has published 200 scientific papers, is an inventor on 60 U.S. patents, and has received two national awards, the ACS Heroes of Chemistry Award (2000) and the ACS Award in Industrial Chemistry (2003). Dr. Maryanoff is a Fellow in the American Association for the Advancement of Science and the Royal Society of Chemistry. Han-Cheng Zhang received B.S. and M.S. degrees in chemistry from Xiamen University, P.R.C., and served as a faculty member there for 5 years. He came to the United States and earned a Ph.D. degree in organic chemistry from Rensselaer Polytechnic Institute (1992), working with Prof. Doyle Daves. He joined the R. W. Johnson Pharmaceutical Research Institute as a Postdoctoral Scientist with Dr. Bruce Maryanoff and, after one year, as a Scientist. Dr. Zhang has worked as a medicinal chemist in the areas of G-protein-coupled receptors, proteases, and kinases to discover new drug candidates, recently leading a project that identified the first potent, selective antagonists for the thrombin receptor, proteaseactivated receptor 1. He is now at the level of Principal Scientist in Johnson & Johnson Pharmaceutical Research & Development. Dr. Zhang has published over 40 scientific papers and is an inventor on 13 U.S. patents (issued or pending). His scientific interests include the design and synthesis of novel therapeutic agents, heterocycles, stereoselective reactions, organometallic chemistry, and solid-phase organic synthesis. Judi...

Although intravenously administered antiplatelet fibrinogen receptor (GPIIb/IIIa) antagonists have become established in the acute-care clinical setting for the prevention of thrombosis, orally administered drugs for chronic use are still under development. Herein, we present details from our exploration of structure-activity surrounding the prototype fibrinogen receptor antagonist RWJ-50042 (racemate of 1), which was derived from a unique approach involving the gamma-chain of fibrinogen (Hoekstra et al. J. Med. Chem. 1995, 38, 1582). Our analogue studies culminated in the discovery of RWJ-53308 (2), a potent, orally active GPIIb/IIIa antagonist. To progress from RWJ-50042 to a suitable candidate for clinical development, we conducted a series of optimization cycles that employed solid-phase parallel synthesis for the rapid, efficient preparation of nearly 250 analogues, which were assayed for fibrinogen receptor affinity and inhibition of platelet aggregation induced by four different activators. This strategy produced several promising analogues for advanced study, including 3-(3,4-methylenedioxybenzene)-beta-amino acid analogue 3 (significant improved in vivo potency) and 3-(3-pyridyl)-beta-amino acid 2 (significantly improved potency, oral absorption, and duration of action). In dogs, 2 displayed significant ex vivo antiplatelet activity on oral administration at 1.0 mg/kg, 16% systemic oral bioavailability, minimal metabolic transformation, and an excellent safety profile. Additionally, 2 was found to be efficacious in three in vivo thrombosis models: canine arteriovenous (AV) shunt (0.01-0.1 mg/kg, iv), guinea pig photoactivation-induced injury (0.3-3 mg/kg, iv), and guinea pig ferric chloride-induced injury (0.3-1 mg/kg, iv). On the basis of its noteworthy preclinical data, RWJ-53308 (2) was selected for clinical evaluation.

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Elarofiban is a novel, nonpeptide, orally active fibrinogen receptor antagonist useful for the treatment of platelet mediated thrombotic disorders (Costanzo, M. J.; Hoekstra, W. J.; Maryanoff, B. E. WO, 97/41102, 1997). Herein we describe the process research that was carried out for the synthesis of elarofiban that eventually led to the development of a safe and cost-effective commercial scale process.

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The importance of p-amino acids and esters for the synthesis of potential therapeutic agents and biologically active compounds is well known and the subject of this special issue. This review outlines some of the recent approaches reported for the synthesis of both racemic and enantiomeric p-amino acids and e ters with emphasis on those used for large scale production. This compilation is written from a chemical process perspective focusing on the practical application of these processes for large scale synthesis. A survey of procedures described in patent publications as well as current advances from chemical process research groups and results from our laboratory are included with emphasis on asymmetric Michael-type additions, addition of metal enolates to imines/sulfinimines, classical and enzymatic resolutions, and reduction of enantiomeric enamines.