Richard A. Nugent

Modifications of C-2 on the pyrroloquinoline template aimed at the development of potent herpesvirus antivirals with improved aqueous solubility

A series of C-2 pyrroloquinoline analogs designed to improve aqueous solubility were examined for herpesvirus polymerase and antiviral activity. Several analogs were identified that maintained the antiviral activity of the previous development candidate against HCMV, HSV-1 and VZV, but with significantly improved aqueous solubility.

Novel benzoxazole inhibitors of mPGES-1.

A novel series of potent benzoxazole mPGES-1 inhibitors has been derived from a hit from a high throughput screen. Compound 37 displays mPGES-1 inhibition in an enzyme assay (0.018 μM) and PGE-2 inhibition in a cell-based assay (0.034 μM). It demonstrates 500- and 2500-fold selectivity for mPGES-1 over COX-2 and 6-keto PGF-1α, respectively. In vivo PK studies in dogs demonstrate 55% oral bioavailability and an 7 h half-life.

Anti-inflammatory/antiarthritic ketonic bisphosphonic acid esters

Bisphosphonate ester 2 is an inhibitor of inflammation, but is devoid of antiarthritic effects. SAR studies on a series of related bisphosphonate esters resulted in compounds 6e, 6i, 6j, and 6m, which exhibited excellent inhibition of an arthritis model, in addition to potent anti-inflammatory effects.

New Anti-Inflammatory/Anti-Arthritic Heterocyclic Bisphosphonates

Abstract. In the course of research toward a safe and effective treatment for rheumatoid arthritis, we identified new pyrazolo[1,5-a]pyrimidine and 4-pyrimidinone bisphosphonate esters, which are potent inhibitors of a murine model of chronic, cutaneous inflammation (delayed type hypersensitivity granuloma) and a murine antigen induced arthritis model. 9a has EC30 values of 0.01 and 0.005 mg/kg respectively and represents a new class of antiinflammatory/antiarthritic bisphosphonate ester.