Carl F. Homnick

Bicyclic pyridones as potent, efficacious and orally bioavailable thrombin inhibitors.

A new class of conformationally constrained thrombin inhibitors is described. These compounds contain a unique bicyclic pyridone scaffold which serves as a P3P2 dipeptide surrogate. The synthesis and antithrombotic activity of these inhibitors is reported.

A Selective Protection of 2,3-Diaminopropionic Acid

Abstract A two step selective protection of 2,3-diaminopropionic acid yields the useful diaminopropionic acid methyl ester 3a. Further manipulation yields 2(S)-(N-benzyloxycarbonylamino)-3-aminopropionic acid methyl ester hydrochloride 5 in >99.9%ee.

Selective and controlled hydrolysis of chloropeptin I. HIV-1 integrase activity of fragments

Abstract Selective amide bond cleavages of chloropeptin I were accomplished using trifluoroacetic acid (TFA), and a mixture of acetic acid, hydrochloric acid and thioglycolic acid. The hydrolysis products maintaining the bicyclic core retained HIV-1 integrase inhibitory activity similar to that of the chloropeptin I. The hydrolysis products and their HIV-1 integrase activities are described.

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.

Evaluation of amino acid-based linkers in potent macrocyclic inhibitors of farnesyl-protein transferase

A series of amino acid-based linkers was used to investigate the effects of various substituents upon the potency, pharmacokinetic properties, and conformation of macrocyclic farnesyl-protein transferase inhibitors (FTIs). As a result of the studies described herein, highly potent FTIs with improved pharmacokinetic profiles have been identified.