Lawrence W. Dillard

Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility.

Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.

Synthesis of 2-amino-5-benzoyl-4-(2-furyl)thiazoles as adenosine A(2A) receptor antagonists.

The discovery and synthesis of a series of 2-amino-5-benzoyl-4-(2-furyl)thiazoles as adenosine A(2A) receptor antagonists from a small-molecule combinatorial library using a high-throughput radioligand-binding assay is described. Antagonists were further characterized in the A(2A) binding assay and an A(1) selectivity assay. Selected examples exhibited excellent affinity for A(2A) and good selectivity versus the A(1) receptor.

Design and Optimization of Renin Inhibitors: Orally Bioavailable Alkyl Amines

Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral administration of lead compound 21l, with MW of 508 and IC(50) of 0.47nM, caused a sustained reduction in mean arterial blood pressure in a double transgenic rat model of hypertension.

Optimization of orally bioavailable alkyl amine renin inhibitors.

Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC(50) of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in >20h reduction of blood pressure in a double transgenic rat model of hypertension.

Binary encoded small-molecule libraries in drug discovery and optimization

A variety of small-molecule combinatorial libraries have been prepared on solid support using a binary encoding strategy employing non-sequenceable encoding molecules. Library members are attached to the support using photolabile linkers which permit their release for assay free in solution. The encoding molecules are attached using a carbene insertion reaction and are released via oxidation. A wide variety of synthetic reactions have been utilized for library synthesis including, for example, cyclocondensations, reductive aminations, and heteroaromatic halide displacements, as well as acylations and sulfonylations. Initial screening of two such libraries identified lead structures for the inhibition of carbonic anhydrase. Subsequently, based upon these leads a smaller focused combinatorial library was constructed and used to analyze the structure-activity relationships (SARs) governing enzyme inhibition and isozyme selectivity. The combination of random screening with a broad diversity of compounds, followed by focused libraries for detailed SARs and selectivity, demonstrates the power of binary encoded small-molecule combinatorial libraries for drug discovery.

Biphenyl/diphenyl ether renin inhibitors: Filling the S1 pocket of renin via the S3 pocket

Structure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several parameters including potency in the presence of human plasma, selectivity against CYP3A4 inhibition and improved rat oral bioavailability led to the identification of 8d which demonstrated antihypertensive efficacy in a transgenic rat model of human hypertension.

1 – High Throughput Analysis of Combinatorial Libraries Encoded with Electrophoric Molecular Tags

Publisher Summary Very valuable resources for the discovery of biologically active agents are encoded combinatorial libraries of small molecules. A binary encoding protocol employing electrophoric molecular tags (ECLiPSe technology) has been developed at Pharmacopeia. A series of quality control (QC) protocols to ensure the highest degree of library has also been put into practice. This protocol, sets of synthons are serially combined through split-and-pool or direct divide synthesis in tandem with the incorporation of binary sets of electrophoric tags on solid support. Quality control steps occur throughout the entire library construction pipeline. To ensure a successful library synthesis and production elution Extensive synthon profiling, rigorous analysis of QC compounds, final confirmation of library chemistry (library QA), and production-in-process-QC analysis are essential. Empirical information regarding overall fidelity and an indication of the performance of individual synthons is provided by both in-line and final library QA. The quality of large, encoded combinatorial libraries can be assessed by library QA, a powerful analytical protocol. Based on the combined application of tag decoding and single bead liquid chromatography/mass spectrometry (LC/MS), QA analysis would be virtually impossible to carry out without an encoding strategy due to redundant masses produced during split synthesis. The statistical theory and its application to library assessment are analogous to the accepted statistical sampling practices used in the industry to ascertain the quality of mass-produced material. The simplicity of tag reading and rapid acquisition of structure activity relationship (SAR) information is arguably the most significant advantage of encoding technology vs. other deconvolution techniques. Library QA serves to substantiate and enhance the value of nascent SAR obtainment from library screening.