Robert J. Lynch

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.

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.

Non-Peptide αvβ3 Antagonists. Part 4: Potent and Orally Bioavailable Chain-Shortened RGD Mimetics

Abstract Potent non-peptidic α v β 3 antagonists have been prepared where deletion of an amide bond from an earlier series of linear RGD-mimetics provides a novel series of chain-shortened α v β 3 antagonists with significantly improved oral pharmacokinetics. These chain-shortened α v β 3 antagonists represent structurally novel integrin inhibitors.

Nonpeptide GPIIb/IIIa inhibitors. 10. Centrally constrained alpha-sulfonamides are potent inhibitors of platelet aggregation

Abstract Potency enhancing features of two series of fibrinogen receptor antagonists were combined to give analogs with improved potency and oral activity. Antagonists containing either alkyl or aryl sulfonamides and a central isoindolinone structural constraint demonstrate high affinity for both activated and unactivated platelet receptors.

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.

Non-peptide fibrinogen receptor antagonists. 3. design and discovery of a centrally constrained inhibitor

Abstract Analysis of platelet aggregation inhibition results and rotational isomer preferences has provided an understanding of inhibitory potency for m-phthalic acid analogs 7–7. Constraint of the N-terminal amide led to compound 9, which is potent, selective, and orally active.

Non-peptide glycoprotein IIb/IIIa inhibitors. 9. Centrally constrained alpha-sulfonamides are useful tools for exploring platelet receptor function

Abstract Two fluorescent, centrally constrained fibrinogen receptor antagonists were prepared to probe ligand receptor interactions.

High-throughput analysis of drug binding interactions for the human cardiac channel, Kv1.5.

The voltage-gated potassium channel Kv1.5 is one of the key regulators of membrane potential repolarization in human atrial myocytes and is considered a potential drug target to treat atrial fibrillation. In this study we sought to determine molecular mechanism of action of DPO-1, a diphenylphosphine oxide derivative recently shown to terminate experimental atrial arrhythmia without affecting ventricular refractory period. In addition, we provided similar analysis for additional two small molecule blockers, representing different structural classes: cyclohexanones (PAC) and nor-triterpenoids (correolide). To rapidly identify the residues within the Kv1.5 channel critical for blocking activity of these molecules, two functional high-throughput ion channel assays were employed together with site-directed mutagenesis. Our study revealed that the residues critical for blocking activity of for DPO-1 include T480, localized at the outer mouth of the pore, and two residues along S6 helix: V505 and I508. The overlapping site was identified for PAC and included residues T480 and V505. In contrast to DPO-1, the I508A mutation resulted in only a modest reduction in the block of Kv1.5 by PAC (9-fold). Correolide, the largest molecule examined, made widespread interactions along the entire length of the pore (from T480 to V516). In summary, we have identified multiple residues involved in forming high affinity binding site for Kv1.5 blockers. Similar approaches of high-throughput ion channel technologies, combined with site-directed mutagenesis, may allow for parallel, rapid and accurate analysis of ion channel interactions with multiple compounds and could facilitate the design of more potent and selective ion channel blockers.

Nonpeptide GPIIB/IIIA inhibitors. 16. Thieno[2,3-b]thiophene α-sulfonamides are potent inhibitors of platelet aggregation

Abstract Centrally constrained thieno[2,3- b ]thiophene sulfonamides have provided a potent, selective, orally active series of platelet aggregation inhibitors. Compound 21 showed excellent activity in the dog after a single oral dose of 200 μg/kg.

Nonpeptide glycoprotein IIB/IIIA inhibitors. 12. Potent and orally active centrally constrained thieno[2,3-c]pyridones

Abstract A series of potent, orally active thieno[2,3-c]pyridone GPIIb/IIIa inhibitors featuring β-alanine C-2 sulfonamide substitution is described.