Carolyn DiIanni Carroll

Identification of potent inhibitors of Plasmodium falciparum plasmepsin II from an encoded statine combinatorial library.

An encoded 13,020-member combinatorial library was synthesized containing a statine core. Evaluation of this library with plasmepsin II, an aspartyl protease required for hemoglobin metabolism in the malaria parasite, led to the identification of potent and selective inhibitors as well as novel structure-activity relationships.

Evaluation of a structure-based statine cyclic diamino amide encoded combinatorial library against plasmepsin II and cathepsin D

A structure-based 18,900-member combinatorial library was synthesized containing a statine template and three cyclic diamino acids as potential P1, P2-P4 surrogates. Evaluation of this encoded library against two aspartyl proteases, plasmepsin II and cathepsin D, led to the identification of selective inhibitors for each enzyme.

III. Identification of novel CXCR3 chemokine receptor antagonists with a pyrazinyl-piperazinyl-piperidine scaffold.

The SAR of a novel pyrazinyl-piperazinyl-piperidine scaffold with CXCR3 receptor antagonist activity was explored. Optimization of the DMPK profile and reduction of hERG inhibition is described. Compound 16e with single-digit CXCR3 affinity, good rat PK and hERG profiles has been identified as a lead for further study.

Novel CXCR3 antagonists with a piperazinyl-piperidine core

High-throughput screening of an encoded combinatorial aryl piperazine library led to the identification of a novel series of potent piperazinyl-piperidine based CXCR3 antagonists. Analogs of the initial hit were synthesized via solid and solution phase methods to probe the influence of structure on the CXCR3 binding of these molecules. Various functional groups were found to contribute to the overall potency and essential molecular features were identified.

Screening Aspartyl Proteases with Combinatorial Libraries

Large numbers of pharmaceutically relevant low-molecular weight compounds can now be synthesized using combinatorial methods. Screening these large libraries of compounds requires high throughput assays. These methods are utilized to search for inhibitors of the aspartyl proteases, plasmepsin II and cathepsin D. Plasmepsin II, a protease found in the malaria parasite, hydrolyzes human hemoglobin, the nutrient source for the parasite and is a new target for anti-malaria therapy. Cathepsin D may be involved in many biological processes and inhibitors would help to clarify the role of cathepsin D in these processes. Plasmepsin II and cathepsin D are approximately 35% identical in amino acid sequence. Therefore, a comparison of the screening results of these two enzymes will be very useful in determining each enzymes specificity and demonstrating the power of utilizing encoded combinatorial libraries.

IV. Discovery of CXCR3 antagonists substituted with heterocycles as amide surrogates: improved PK, hERG and metabolic profiles.

The structure-human CXCR3 binding affinity relationship of a series of pyridyl/pyrazinyl-piperazinyl-piperidine derivatives were explored with a focus to improve PK, hERG and metabolic profiles. Several small heterocycles were identified as amide surrogates, which minimized many potential metabolite issues. During the course of SAR development, we have observed the additive effect of desirable functional groups to improve hERG and PK profiles which lead to the discovery of many clinically developable CXCR3 antagonists with excellent overall profile.