Judith H. Cohen

Solid-phase parallel synthesis applied to lead optimization: Discovery of potent analogues of the GPIIb/IIIa antagonist RWJ-50042

Abstract A study of β-turn peptide mimetics, related to the C-terminal γ-chain of fibrinogen and containing a nipecotic acid scaffold, led to RWJ-50042 (1), an interesting fibrinogen receptor (GPIIb/IIIa) antagonist. To enhance potency, we employed solid-phase parallel synthesis for the preparation of over 200 analogues in a protocol of optimization cycles. This strategy produced several promising nipecotamide analogues, such as 25, which is 35 times more potent than 1 in vitro.

Hydrolysis of polypeptide esters with tetrabutylammonium hydroxide

Abstract Tetrabutylammonium hydroxide is effective in hydrolysis of polypeptide esters to the corresponding acids with minimum racemization of the stereogenic centers at the α-positions. It is especially effective in hydrolysis of non-polar polypeptide esters that are insoluble in most common solvents.

An efficient stereoselective synthesis of methyl (S)-3-amino-3-(3-pyridyl)propanoate

Methyl (S)-3-amino-3-(3-pyridyl)propanoate (2) is a key starting material in the synthesis of RWJ-53308 (1), an orally active antagonist of the platelet fibrinogen receptor (GP IIb/IIIa antagonist). Herein, we describe an efficient stereoselective synthesis of 2 by the hydrogenation of enantiomeric enamine 8 with Pd(OH)2C, followed by the removal of the chiral auxiliary under mild conditions, a novel procedure that employs the combination of formic acid and triethylsilane.

Mass balance in rapamycin autoxidation.

The immunosuppressant drug rapamycin is a complex polyene-containing natural product which undergoes autoxidation. The resulting product mixtures contained numerous monomeric and oligomeric compounds, which represented challenges for addressing mass balance in forced degradation studies and in analysis of aged developmental drug-eluting stents. A combination of SEC with ultraviolet and refractive index detection and RP-HPLC was used to account for drug loss and product formation. The mass balance methodology was subsequently validated for the determination of rapamycin and composite rapamycin autoxidation product material in developmental stent samples. This mass balance approach may find general applicability in other situations where drugs degrade to a plethora of products, which cannot be determined individually and summed.

Quantitative surface defect analysis of drug-eluting coronary stents by scanning electron microscopy: coating integrity of the CYPHER® Sirolimus-eluting Coronary Stent

A method was developed to assess the durability of drug-polymer coatings, such as those found on drug-eluting stents (DES). The method is based on scanning electron microscopy (SEM) and intensity threshold detection for converting qualitative SEM images to quantification of defects on a DES surface. Previously, a method was developed to fatigue stents by subjecting them to pulsatile loading conditions. The particles generated during fatigue testing were captured and evaluated for chemistry, size, and quantity. The amount of particulates observed from a commercially available DES product was low and on the same order of magnitude as the blanks/controls after acute and chronic simulated in vitro fatigue testing. These results are confirmed using the method developed in this work by evaluating the stent surface before and after chronic fatigue cycling. The relative change in surface defect area during the entire pulsatile fatigue testing was insignificant (<3%), indicating the polymer coating maintains remarkable durability even when subjected to deployment, overexpansion, and repetitive fatigue cycling. Further chemical analysis by FTIR microscopy of individual particles supports the claim that the polymer coating does not shed appreciably during the testing.

A test method to evaluate chronic particulate generation from durable polymer stent coatings: a case study of CYPHER® sirolimus-eluting coronary stents

In order to predict the long term coating durability of drug-eluting stent (DES) products, we developed a new testing methodology using a novel mechanical tester to evaluate the potential of drug–polymer coatings to generate particles over time. The tester simulates the device radial fatigue expected during in vivo conditions due to expansion and contraction of the implanted vessel. Analysis by Scanning Electron Microscopy (SEM) of particulate collected via an in-line filtration system allows for evaluation of the chronic durability of DES polymer coatings. Data provided within show the durable polymer coating of CYPHER® Stents generates small amounts of particulates upon fatigue indicating coating integrity is maintained even when the DES system is subjected to expansion, deployment, and repetitive cycling modalities.