Bryan K. Sorensen

Discovery and SAR of diarylsulfide cyclopropylamide LFA-1/ICAM-1 interaction antagonists

Diarylsulfide cyclopropylamides were synthesized and evaluated as LFA-1/ICAM-1 interaction antagonists. A substituent pattern was identified which maximized potency and minimized protein binding as exemplified by antagonist 30 (IC50 = 5 nM).

An evaluation of a C-glucuronide as a liver targeting group: conjugate of a glucocorticoid antagonist.

A beta-C-glucuronide conjugate of the glucocorticoid receptor antagonist, Mifepristone 1, was prepared which maintained binding affinity, had modest in vitro activity, and was metabolically more stable than the parent. Pharmacokinetic studies suggest that the conjugate is recognized by the liver like O-glucuronides and may undergo a portion of the enterohepatic recirculation loop.

Discovery of a series of pyrrolidine-based endothelin receptor antagonists with enhanced ETA receptor selectivity

Endothelins, ET-1, ET-2, and ET-3 are potent vasoconstricting and mitogenic 21-amino acid bicyclic peptides, which exert their effects upon binding to the ET(A) and ET(B) receptors. The ET(A) receptor mediates vasoconstriction and smooth muscle cell proliferation, and the ET(B) receptor mediates different effects in different tissues, including nitric oxide release from endothelial cells, and vasoconstriction in certain vascular cell types. Selective antagonists of endothelin receptor subtypes may prove useful in determining the role of endothelin in various tissue types and disease states, and hence as therapeutic agents for such diseases. The pyrrolidine carboxylic acid A-127722 has been disclosed as a potent and ET(A)-selective antagonist, and is currently undergoing clinical trials. In our efforts to find antagonists with altered selectivity (ET(A)-selective, ET(B)-selective, or nonselective), we investigated the SAR of the 2-substituent on the pyrrolidine. Compounds with alkyl groups at the 2-position possessed ET(A) selectivity improved over A-127722 (1400-fold selective), with the best of these compounds showing nearly 19,000-fold selectivity.

Synthesis and In Vitro evaluation of fused ring heterocyle-containing angiotensin II antagonists.

Abstract Fused ring heterocyclic analogs of A-81080 (pA2= 9.9) were synthesized and their activities in the rabbit aorta in vitro assay were measued. The best compounds (pA2 = 8.6) in series 1 had R1 = Et, R2 = H, W = X = Z = C-H, and Y = C-OMe or C-COOH. In series 2, the best compound (pA2 = 8.3) had R1 = Et, R2 = H, W = N-Me, X = C-H, and Y = N.

2-Butyl-4-iodoimidazole-5-carboxaldehyde: A Versatile Intermediate for the Synthesis of Highly Functionalized Imidazoles

Abstract The facile preparation of 2-butyl-4-iodoimidazole-5-carboxaldehyde 1 is described. The versatility of this intermediate in the synthesis of highly tunctionalized imidazoles is demonstrated with the synthesis of two potent and selective angiotensin II receptor antagonists.

Abstract A245: Imidazo[2,1‐b]thiazole and imidazo[1,2‐a]pyridine amides as novel inhibitors of the insulin‐like growth factor (IGF1R) and members of the epidermal growth factor family of tyrosine kinases

The insulin‐like growth factor 1 receptor (IGF1R) and its ligands, IGF1 and IGF2 are associated with cell growth and resistance to apoptosis. The ErbB axis, consisting of 4 receptor tyrosine kinases (EGFR, ErbB2, ErbB3, and ErbB4) is a longstanding target of cancer chemotherapy. There is a growing body of literature suggesting that targeting a combination of the IGF and ErbB axes would be more effective than targeting either alone. A screen of Abbott9s compound collection revealed a scaffold, the imidazothiazoles, which showed activity against EGFR. A similar scaffold from the literature had previously been reported to have IGF1R activity. Optimization of the imidazothiazoles, and a scaffold hop to imidazopyridines, has provided a series of compounds with amide head groups with kinase inhibitory activity against IGF1R, EGFR, and ErbB2. These compounds also demonstrated inhibition of p‐IGF1R and p‐EGFR in a human epidermoid carcinoma line (A‐431), as well as inhibition of p‐ErbB2 in a human gastric cancer cell line (N87). This poster will discuss the synthesis and optimization of the imidazothiazoles and imidazopyridines as multitargeted kinase inhibitors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A245.