James Samanen

Development of GPIIb/IIIa antagonists as antithrombotic drugs

Thrombosis represents a major target for development of drugs to prevent and treat a variety of cardiovascular and cerebrovascular diseases, which are the leading cause of morbidity and mortality in the Western world. This review by Andy Nichols and colleagues focuses on a central process in thrombosis, namely platelet aggregation, and how it can be inhibited by antagonists of the adhesion molecule GPIIb/IIIa. Successful and future therapeutic applications of GPIIb/IIIa antagonists, and their pharmacology, are considered in detail.

Enantiospecific synthesis of SB 214857, a potent, orally active, nonpeptide fibrinogen receptor antagonist

Abstract An enantiospecific synthesis of SB 214857, a potent, nonpeplide fibrinogen receptor antagonist, is reported. The synthetic route employs as a key step an intramolecular aryl fluoride displacement to form the sevenmembered ring of the 1,4-benzodiazepine system.

Combinatorial chemistry. Use of an intramolecular ruthenium catalyzed olefin/alkyne metathesis reaction in tandem with a Diels-Alder cycloaddition reaction to construct functionalized hexahydroisoindoles

Abstract We show here the first example of a ruthenium catalyzed ene-yne metathesis reaction in tandem with a Diels-Alder cycloaddition reaction to efficiently form highly substituted hexahydroisoindole ring systems on Wang resin. This approach was used to prepare a 4200 membered combinatorial library.

Chemical Approaches to Improve the Oral Bioavailability of Peptidergic Molecules

This review discusses both tools and strategies that may be employed as approaches towards the pursuit of orally active compounds from peptidergic molecules. Besides providing a review of these subjects, this paper provides an example of how these were utilized in a research programme at SmithKline Beecham involving the development of orally active GPIIb/IIIa antagonists. The tools for studying oral drug absorption in‐vitro include variants of the Ussing chamber which utilize either intestinal tissues or cultured epithelial cells that permit the measurement of intestinal permeability. Example absorption studies that are described are mannitol, cephalexin, the growth hormone‐releasing peptide SK&F 110679 and two GPIIb/ IIIa antagonist peptides SK&F 106760 and SK&F 107260. With the exception of cephalexin, these compounds cross the intestine by passive paracellular diffusion. Cephalexin, on the other hand, crosses the intestine via the oligopeptide transporter. Structure‐transport studies are reviewed for this transporter. The tools for studying oral drug absorption in‐vivo involve animals bearing in‐dwelling intestinal or portal vein catheters. A study of the segmental absorption of SK&F 106760 is provided.

Design of a potent and orally active nonpeptide platelet fibrinogen receptor (GPIIb/IIIa) antagonist.

The direct design of the potent nonpeptide platelet fibrinogen receptor (GPIIb/IIIa) antagonist, 8-[[[4- (aminoiminomethyl)phenyl]amino]carbonyl]-2,3,4,5-tetrahydro-3-oxo- 4- (2-phenylethyl)-1H-1,4-benzodiazepine-2-acetic acid, (3) (SB 207448), based on the structure and conformation of the potent and highly constrained cyclic peptide antagonist SK&F 107260 (2), has been reported [Ku et al., J. Am. Chem. Soc. 1993, 115, 8861]. While 3 displayed in vivo activity in the conscious dog following intravenous administration, it was not active following intraduodenal administration; activity was measured with an ex vivo platelet aggregation assay. The secondary amide in 3 was N-methylated in the expectation of increased absorption and bioavailability. The resulting tertiary amide, 4 (SB 208651), also showed high binding affinity for human GPIIb/IIIa and potent antiaggregatory activity in human platelet-rich plasma. Most importantly, 4 was active in vivo following intravenous and intraduodenal administration. Comparison of the iv and id inhibition curves suggests an apparent bioavailability of approximately 10%. Thus, 4 represents the first orally active compound in this series of potent, nonpeptide fibrinogen receptor antagonists.

Discovery of an imidazopyridine-containing 1,4-benzodiazepine nonpeptide vitronectin receptor (αvβ3) antagonist with efficacy in a restenosis model

In the 3-oxo-1,4-benzodiazepine-2-acetic acid series of vitronectin receptor (αvβ3) antagonists, a compound containing an imidazopyridine arginine mimetic was discovered which had sufficient potency and iv pharmacokinetics for demonstration of efficacy in a rat restenosis model.

Refinement of a molecular model of angiotensin II (AII) employed in the discovery of potent nonpeptide antagonists

Abstract A novel conformational model of AII, Model II, had been employed previously in the design of potent benzylimidazole AII antagonists (J. Med. Chem. 1991, 34, 1514–1517). This paper considers this model in relation to the recently described potent AII analogs [hCys3,5]-AII, and [Sar1,hCys3,5,IIe8]-AII. Conformational analysis of Ac-S,S-cyclo-(hCys-Ala-hCys)-NH2 suggests a family of modified conformations for AII, Model III, which retains the topological arrangement of functional groups in Model II that had been employed in nonpeptide analog design.

Phenylbutyrates as potent, orally bioavailable vitronectin receptor (integrin αvβ3) antagonists

In our continuing efforts to identify small molecule vitronectin receptor antagonists, we have discovered a series of phenylbutyrate derivatives, exemplified by 16, which have good potency and excellent oral bioavailability (approximately 100% in rats). This new series is derived conceptually from opening of the seven-membered ring of SB-265123.

Structure-activity relationships in 3-oxo-1,4-benzodiazepine-2-acetic acid GPIIb/IIIa antagonists. The 2-benzazepine series

Abstract In an investigation of the contribution of N-1 to the binding, antiaggregatory, and oral activity in 3-oxo-1,4-benzodiazepine-2-acetic acid based GPIIb/IIIa antagonists, a series of 2-benzazepine analogs, wherein N-1 of the 1,4-benzodiazepine nucleus has been replaced by a methylene group, was examined.

Similarities and differences in the discovery and use of biopharmaceuticals and small-molecule chemotherapeutics

Biotechnology has given rise to a broad range of biotherapies or biologics, including biomolecular drugs, vaccines, cell or gene therapies. This chapter focuses on biomolecular drugs, namely monoclonal antibodies (Mabs), cytokines, tissue growth factors and therapeutic proteins. Prior to the US approval of recombinant human insulin in 1982, biomolecular drugs were extracted from natural sources. The tools of molecular biology have dramatically increased the discovery and development of new biopharmaceuticals. The most obvious difference between small-molecule drugs (SMDs) and biomolecular drugs is size, like the difference in weight between a bicycle and a business jet. SMDs and biomolecular drugs are compared in this chapter by structure, molecular weight, preparation, physicochemical properties, and route of administration, as well as distribution, metabolism, serum half-life, dosing regimen, species reactivity, antigenicity & hypersensitivity, clearance mechanisms, drug–drug interactions, and pharmacology. This chapter reviews the differences and similarities in the various stages of drug discovery and development, with respect to cost, probability of success and cycle time. The clinical metrics of overall clinical success rate, stage-related success rate, and clinical cycle time are examined for SMDs and biomolecular drugs. The hybrid class of peptide drugs tends to be equated with biologics, due to their amino acid content and because oral activity is rare. But peptides truly bridge the gap between small molecules and biologics, in terms of physical properties, range of therapy areas and means of production. This chapter summarizes the similarities and differences of peptide drugs with SMDs and biomolecular drugs. The manner in which these agents compare as products with respect to manufacturing and pricing are considered. Two case studies are presented—the antagonists where small-molecule, peptide and Mab agents have competed in the market, and Her2 inhibitors where small-molecule and Mab agents may ultimately synergize as a combination product. Biomolecular drugs have levelled the playing field. All the “big Pharma” companies now have the capacity to develop both types of drugs. Conversely the larger biotech companies are developing the capacity for small-molecule synthesis. Now, with many blockbuster biologics nearing patent expiration, biosimilars are on the way. Its no longer a question of “choose which type”—one will need to know how to discover and develop either type of drug.