Cullen L. Cavallaro

Discovery of the CCR1 antagonist, BMS-817399, for the treatment of rheumatoid arthritis.

High-affinity, functionally potent, urea-based antagonists of CCR1 have been discovered. Modulation of PXR transactivation has revealed the selective and orally bioavailable CCR1 antagonist BMS-817399 (29), which entered clinical trials for the treatment of rheumatoid arthritis.

Synthesis and structure–activity relationships of novel indazolyl glucocorticoid receptor partial agonists

SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors.

The discovery of BMS-457, a potent and selective CCR1 antagonist

A series of compounds which exhibited good human CCR1 binding and functional potency was modified resulting in the discovery of a novel series of high affinity, functionally potent antagonists of the CCR1 receptor. Issues of PXR activity, ion-channel potency, and poor metabolic stability were addressed by the addition of a hydroxyl group to an otherwise lipophilic area in the molecule resulting in the discovery of preclinical candidate BMS-457 for the treatment of rheumatoid arthritis.

Discovery and Lead Optimization of a Novel Series of CC Chemokine Receptor 1 (CCR1)-Selective Piperidine Antagonists via Parallel Synthesis

A series of novel, potent CCR1 inhibitors was developed from a moderately active hit using an iterative parallel synthesis approach. The initial hit (composed of three subunits: an amine, a central amino acid, and an N-terminal cap) became the basis for a series of parallel chemical libraries designed to generate SAR data. Libraries were synthesized that explored each of the three subunits; the CCR1 binding data obtained revealed the following: (1) changes to the amine are not well tolerated; (2) small alkylamino acids are preferred in the center of the molecule; (3) substitutions at the N-terminus are generally well tolerated. These data were used to drive the optimization of the series, ultimately providing a lead with a CCR1 binding IC(50) of 28 nM (48). This lead demonstrates high selectivity for CCR1 over other CCR-family members, high microsomal stability, and good pharmacokinetics in mice.

Pseudosaccharin amines as potent and selective KV1.5 blockers

Phenethyl aminoheterocycles like compound 1 were known to be potent I(Kur) blockers although they lacked potency in vivo. Modification of the heterocycle led to the design and synthesis of pseudosaccharin amines. Compounds such as 14, 17d and 21c were found to be potent K(V)1.5 blockers and selective over other cardiac ion channels. These compounds had potent pharmacodynamic activity, however, they also showed off-target activities such as hemodynamic effects.

4.14 – Library Design: Ligand and Structure-Based Principles for Parallel and Combinatorial Libraries

Diversity has historically played a critical role in the design of combinatorial libraries, screening sets, and corporate collections for lead discovery. Large library design in the 1990s ranged from arbitrary through property-based reagent selection to product-based approaches. Over time, however, there has been a downward trend in library size as information about the desired targets increased due to the genomics revolution and the increasing availability of target protein structures from crystallography and homology modeling. Concurrently, computing grids and central processing unit (CPU) clusters have facilitated the development of structure-based tools that screen hundreds of thousands of molecules. Smaller ‘smarter’ combinatorial and focused parallel libraries have replaced those unfocused large libraries in the twenty-first-century drug design paradigm. While diversity-derived libraries still play a role in lead discovery, expectations for their success in other areas of drug discovery were generally unrealized and contributed to the current dominance of target family and target-specific approaches in library design. This chapter reviews methods for both combinatorial and array-based library design with an emphasis on the design of the various types of focused libraries.