Nathan C. Ihle

Nonpeptide αvβ3 antagonists. Part 2: constrained glycyl amides derived from the RGD tripeptide

Abstract Mimetics of the RGD tripeptide are described that are potent, selective antagonists of the integrin receptor, αvβ3. The use of the 5,6,7,8-tetrahydro[1,8]naphthyridine group as a potency-enhancing N-terminus is demonstrated. Two 3-substituted-3-amino-propionic acids previously contained in αIIbβ3 antagonists were utilized to enhance binding affinity and functional activity for the targeted receptor. Further affinity increases were then achieved through the use of cyclic glycyl amide bond constraints.

Nicotinamide N-oxides as CXCR2 antagonists.

A series of nicotinamide N-oxides was synthesized and shown to be novel, potent, and selective antagonists of the CXCR2 receptor. Furthermore, these compounds showed significant functional activity against GRO-alpha-driven human neutrophil chemotaxis. Compounds of this class may be useful for the treatment of inflammatory, auto-immune, and allergic disorders.

Nicotinanilides as inhibitors of neutrophil chemotaxis

A series of 4-fluoronicotinanilides was synthesized and shown to be novel, potent, and selective inhibitors against GRO-alpha-driven human neutrophil chemotaxis. Compounds of this class may be useful for the treatment of inflammatory, autoimmune, and allergic disorders.

Pharmacokinetics and Pharmacodynamics of L-703,014, a Potent Fibrinogen Receptor Antagonist, After Intravenous and Oral Administration in the Dog

The pharmacokinetics and pharmacodynamics of L-703,014, a fibrinogen receptor antagonist, have been examined in the dog. An analytical method which utilizes methanol precipitation of dog plasma proteins followed by HPLC with an automated column switching technique using the chemical analogue L-704,326 as internal standard was developed for the determination of L-703,014 in dog plasma. The compound was not metabolized in the dog and was eliminated in the kidneys and into bile. Of the administered dose, 68.9 ± 1.3% (i.v.) and 80.5 ± 11.9% (p.o.) were recovered in the feces; 20.3 ± 3% (i.v.) and 2.2 ± 0.2% (p.o.) were recovered in the urine by 72 hr. L-703,014 was 23 ± 3.4% bound in dog plasma protein and the mean ratio of plasma/whole blood was 1.22 ± 0.05. The mean terminal half-life was 118 ± 36 min, the mean steady-state volume of distribution was 0.61 ± 0.22 L/kg, and the mean plasma clearance was 8 ± 2 mL/min/kg. Ex vivo platelet aggregation measurements were made by inducing platelet aggregation with 10 µg/ mL collagen in the presence of 1 µM epinephrine as an agonist. The mean C50 was 44.4 ± 6.0 ng/mL, and the mean Hill coefficient was 1.5 ± 0.3. The mean bioavailability was 4.9 ± 1.4% in dogs administered 2.0 mg/kg (p.o.).

Nonpeptide GPIIB/IIIA receptor antagonists. Part 21: C-6 flexibility and amide bond orientation are important factors in determining the affinity of compounds for activated or resting platelet receptors.

Compound affinity for activated and resting GPIIb/IIIa receptors may differ, and comparison of those differences determines selectivity. Structural features that influence selectivity are discussed.