Edward W. Petrillo

Case study: impact of technology investment on lead discovery at Bristol–Myers Squibb, 1998–2006

We review strategic approaches taken over an eight-year period at BMS to implement new high-throughput approaches to lead discovery. Investments in compound management infrastructure and chemistry library production capability allowed significant growth in the size, diversity and quality of the BMS compound collection. Screening platforms were upgraded with robust automated technology to support miniaturized assay formats, while workflows and information handling technologies were streamlined for improved performance. These technology changes drove the need for a supporting organization in which critical engineering, informatics and scientific skills were more strongly represented. Taken together, these investments led to significant improvements in speed and productivity as well a greater impact of screening campaigns on the initiation of new drug discovery programs.

Dual metalloprotease inhibitors. I. constrained peptidomimetics of mercaptoacyl dipeptides

Abstract A series of benzo-fused lactams were incorporated as conformationally restricted dipeptide mimetics of Ala-Pro in dual-acting ACE/NEP inhibitors 1 and 2. The result of this modification led to compounds possessing excellent inhibitory potency versus ACE and NEP both in vitro and in vivo.

MERCAPTOACYL DIPEPTIDES AS DUAL INHIBITORS OF ANGIOTENSIN-CONVERTING ENZYME AND NEUTRAL ENDOPEPTIDASE PRELIMINARY STRUCTURE-ACTIVITY STUDIES

Abstract Mercaptoacyl dipeptides were prepared as dual-acting ACE/NEP inhibitors. Inhibition of each enzyme may be explained by different binding models. Structure-activity studies determined that, in this series of compounds, the mercaptopropanoyl dipeptide framework leads to increased affinity for NEP but diminished ACE activity in vivo .

Dual metalloprotease inhibitors. IV. Utilization of thiazepines and thiazines as constrained peptidomimetic surrogates in mercaptoacyl dipeptides

Abstract A structure-activity study of the dual acting ACE/NEP inhibitors related to 1a and 1b was undertaken to determine the parameters critical for activity versus ACE and NEP in vitro.

Orally active prodrugs of quinoline-4-carboxylic acid angiotensin II receptor antagonists

Abstract Prodrug derivatization of a potent quinoline-4-carboxylic acid angiotensin II receptor antagonist was Undertaken as an approach to achieve improved oral activity. A dioxolenone carboxylic ester and an alkylated tetrazole prodrug both showed greater oral antihypertensive acivity in the salt-deplete spontaneously hypertensive rat and increased oral bioavailability relative to the parent compound.

1,4-substituted indoles: a potent and selective class of angiostensin II receptor antagonists

The syntheses and pharmacological activity of a series of 1,4-substituted indoles which function as nonpeptidic antagonists of the angiotensin II (AII) receptor are described. Compounds in this series are orally active and demonstrate long lasting antihypertensive activity.

Multiplexing a High-Throughput Liability Assay to Leverage Efficiencies

In order to identify potential cytochrome P-450 3A4 (drug-metabolizing enzyme) inducers at an early stage of the drug discovery process, a cell-based transactivation high-throughput luciferase reporter assay for the human pregnane X receptor (PXR) in HepG2 cells has been implemented and multiplexed with a viability end point for data interpretation, as part of a Lead Profiling portfolio of assays. As a routine part of Lead Profiling operations, assays are periodically evaluated for utility as well as for potential improvements in technology or process. We used a recent evaluation of our PXR-transactivation assay as a model for the application of Lean Thinking-based process analysis to lab-bench assay optimization and automation. This resulted in the development of a 384-well multiplexed homogeneous assay simultaneously detecting PXR transactivation and HepG2 cell cytotoxicity. In order to multiplex fluorescent and luminescent read-outs, modifications to each assay were necessary, which included optimization of multiple assay parameters such as cell density, plate type, and reagent concentrations. Subsequently, a set of compounds including known cytotoxic compounds and PXR inducers were used to validate the multiplexed assay. Results from the multiplexed assay correlate well with those from the singleplexed assay formats measuring PXR transactivation and viability separately. Implementation of the multiplexed assay for routine compound profiling provides improved data quality, sample conservation, cost savings, and resource efficiencies.

Diol sulfonamides: A potent and novel class of inhibitors of human renin

Abstract The syntheses and pharmacological activity of a series of diol sulfonamides which function as inhibitors of human renin are described. The most potent compound in this series, compound 20 (SQ 33,800 ), is a subnanomolar inhibitor of human renin (IC 50 = 0.35 × 10 −9 M).

Case Study: Fosinopril

Fosinopril is an acyloxyalkyl ester of fosinoprilat, a phosphinic acid angiotensin-converting enzyme (ACE) inhibitor developed for the treatment of hypertension and congestive heart failure. The hydroxylphosphinylacetyl proline class of inhibitors exhibits high affinity for ACE and a high degree of efficacy for inhibition of the angiotensin I-induced pressor response in animals (Krapcho et al., 1988) when administered intravenously. These inhibitors exhibited a low level of activity upon oral administration, which could be attributed to low oral absorption. The propanoyloxy isobutyl ester of the trans-4-cyclohexyl proline analog exhibited improved oral activity and long duration of action (DeForrest et al., 1989) and was advanced into preclinical and clinical development (Duchin, 1991).