David A. Claremon

Nonpeptide glycoprotein IIb/IIIa inhibitors: substituted quinazolinediones and quinazolinones as potent fibrinogen receptor antagonists.

The synthesis and biological activity of a series of 3,6-substituted quinazolinediones and quinazolinones are described. The potent activity of these compounds as platelet aggregation inhibitors demonstrates the utility of these structures as central templates for nonpeptide RGD mimics.

Orally Efficacious NR2B-Selective NMDA Receptor Antagonists

A novel series of benzamidines was synthesized and shown to exhibit NR2B-subtype selective NMDA antagonist activity. Compound 31 is orally active in a carrageenan-induced rat hyperalgesia model of pain and shows no motor coordination side effects.

Pyridazine based inhibitors of p38 MAPK

Trisubstituted pyridazines were synthesized and evaluated as in vitro inhibitors of p38MAPK. The most active isomers were those possessing an aryl group alpha and a heteroaryl group beta relative to the nitrogen atom in the 2-position of the central pyridazine. Additionally, substitution in the 6-position of the central pyridazine with a variety of dialkylamino substituents afforded a set of inhibitors having good (p38 IC50 1-20 nM) in vitro activity.

Non-peptide glycoprotein IIb/IIIa inhibitors. 6. Design and synthesis of rigid, centrally constrained non-peptide fibrinogen receptor antagonists

Abstract Low molecular weight non-peptide inhibitors of platelet aggregation based on rigid bicyclic scaffolds are described. Consideration of the reported conformational preferences of 1-alkyl-3-carbonyl pyrroles led to the synthesis of pyrrolopiperazinone 2a which was shown to be a potent, selective antagonist.

Nonpeptide glycoprotein IIb/IIIa inhibitors. 13. design and synthesis of an orally active pyrazolopiperazinone nonpeptide fibrinogen receptor antagonist

Abstract The synthesis and antiplatelet activity of a series of pyrazolopiperazinone nonpeptide fibrinogen receptor antagonists is reported. The sulfonamide analog 6 (L-734, 115), significantly inhibited ex vivo platelet aggregation 24 h after oral administration at doses of 1.0 and 2.0 mg/kg to dogs and rhesus monkeys, respectively.

Preparation of 3-amino-1,4-benzodiazepin-2-ones via direct azidation with trisyl azide

Abstract An efficient synthesis of 3-amino-1,4-benzodiazepin-2-ones utilizing triisopropylbenzenesulfonyl azide (trisyl azide) for the direct azidation of 1,4-benzodiazepin-2-ones is described.

Novel 5-cyclopropyl-1,4-benzodiazepin-2-ones as potent and selective IKs-blocking class III antiarrhythmic agents

Novel 5-cyclopropyl-1,4-benzodiazepin-2-ones having various N-l substituents were identified as potent and selective blockers of the slowly activating cardiac delayed rectifier potassium current (I(Ks)). Compound 11 is the most potent I(Ks) channel blocker reported to date.

Synthesis and evaluation of novel tricyclic benzo[4.5]cyclohepta[1.2]pyridine derivatives as NMDA/NR2B antagonists

A novel series of annulated tricyclic compounds was synthesized and evaluated as NMDA/NR2B antagonists. Structure-activity development was directed towards in vitro optimization of NR2B activity and selectivity over the hERG K(+) channel. Preferred compounds were subsequently evaluated for selectivity in an alpha(1)-adrenergic receptor binding counter-screen and a cell-based assay of NR2B activity.