Larry D. Bratton

Thermodynamic and Structure Guided Design of Statin Based Inhibitors of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase

Clinical studies have demonstrated that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) inhibitors, are effective at lowering mortality levels associated with cardiovascular disease; however, 2-7% of patients may experience statin-induced myalgia that limits compliance with a treatment regimen. High resolution crystal structures, thermodynamic binding parameters, and biochemical data were used to design statin inhibitors with improved HMGR affinity and therapeutic index relative to statin-induced myalgia. These studies facilitated the identification of imidazole 1 as a potent (IC 50 = 7.9 nM) inhibitor with excellent hepatoselectivity (>1000-fold) and good in vivo efficacy. The binding of 1 to HMGR was found to be enthalpically driven with a Delta H of -17.7 kcal/M. Additionally, a second novel series of bicyclic pyrrole-based inhibitors was identified that induced order in a protein flap of HMGR. Similar ordering was detected in a substrate complex, but has not been reported in previous statin inhibitor complexes with HMGR.

Synthesis and structure-activity relationships for a series of substituted pyrrolidine NK1/NK2 receptor antagonists

Abstract We recently described the synthesis and characterization of MDL 105,212, a non peptide tachykinin antagonist with high affinity for NK1 and NK2 receptors.1 Here we report the synthesis and structure-activity relationships for a series of analogs of MDL 105,212 with regards to: NK1 and NK2 receptor binding affinity, physical-chemical characterization; in vitro absorption potential; in vitro metabolic stability; and efficacy in a capsaicin-challenge conscious guinea pig model after oral administration.

Synthesis and sar of 4-(1H-benzimidazole-2-carbonyl)piperidines with dual histamine H1/tachykinin NK1 receptor antagonist activity

Abstract A series of 4-(1H-benzimidazole-2-carbonyl)piperidines with dual histamine H1/tachykinin NK1 receptor antagonist activity has been prepared. Factors affecting receptor binding affinities and oral activity in this series are described.

Discovery of a series of 2-(1H-pyrazol-1-yl)pyridines as ALK5 inhibitors with potential utility in the prevention of dermal scarring.

A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFβ receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFβ induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.

Use of CoMFA in validating the conformation used in designing 4-(1H-benzimidazole-2-carbonyl)piperidines with H1/NK1 receptor antagonist activity

Abstract Support for the conformation used in the design of a series of 4-(1 H -benzimidazole-2-carbonyl)piperidines with dual histamine H 1 /tachykinin NK 1 receptor antagonist activity has been presented. Comparative Molecular Field Analysis(CoMFA) for both receptor binding affinites of the series as well as overlays with several crystal structures of selective receptor antagonists support the conformation.