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Insulin Sensitizing Pharmacology of Thiazolidinediones Correlates with Mitochondrial Gene Expression rather than Activation of PPARγ
TLDR
Important pharmacology of the insulin sensitizing TZDs may involve acute actions, perhaps on the mitochondria, that are independent of direct activation of the nuclear receptor PPARγ. Expand
Discovery and SAR of PF-4693627, a potent, selective and orally bioavailable mPGES-1 inhibitor for the potential treatment of inflammation.
TLDR
A novel series of orally active, selective benzoxazole piperidinecarboxamides as mPGES-1 inhibitors is discovered, including 23, 26, and 29, which were effective in a carrageenan-stimulated guinea pig air pouch model of inflammation. Expand
Stereochemical requirements for the mineralocorticoid receptor antagonist activity of dihydropyridines.
TLDR
Small molecule X-ray crystal structures showed that the C4 stereochemistry of optimized selective MR analogues, e.g. 5, is consistent with MR-active mebudipine, and molecular modeling supports a binding pose consistent with that previously proposed for DHP diesters. Expand
Synthesis and biological evaluation of substituted benzoxazoles as inhibitors of mPGES-1: use of a conformation-based hypothesis to facilitate compound design.
TLDR
The design, synthesis, mPGES-1 activity and in vivo PK of a novel set of substituted benzoxazoles are described and a conformation-based hypothesis for mPGE(2) synthase1 activity based on the preferred conformation of the cyclohexane ring within this class of inhibitors is described. Expand
Thiazolidinediones inhibit the progression of established hypertension in the Dahl salt-sensitive rat
TLDR
The data demonstrate that these TZDs lower blood pressure significantly in Dahl rats and suggest that it may be possible to find insulin-sensitising agents that have beneficial cardiovascular pharmacology with broad applications for disease prevention. Expand
Thermolysis of a Tertiary Alkoxyamine. Recombination and Disproportionation of α-Phenethyl/Diethyl Nitroxyl Radical Pairs
Alkoxyamine 3 undergoes thermolysis only on heating to over 150 °C, ΔH⧧ = 34.3 ± 1.6 kcal/mol and ΔS⧧ = 0.8 ± 3.7 eu. The initially formed nitroxyl (6) and α-phenethyl radicals (5) mainlyExpand
Discovery of (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (PF-3882845), an orally efficacious mineralocorticoid receptor (MR) antagonist
TLDR
A novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (MR) that show excellent potency and selectivity against other nuclear receptors that were discovered by incorporation of a single carboxylate moiety. Expand
Discovery of novel cyanodihydropyridines as potent mineralocorticoid receptor antagonists.
TLDR
The structure-activity relationships of this novel series of cyano ester dihydropyridines resulted in R6 substituted analogues with improved metabolic stability while maintaining excellent MR antagonist activity and selectivity against other nuclear receptors. Expand
Identification of (R)-6-(1-(4-cyano-3-methylphenyl)-5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl)-2-methoxynicotinic acid, a highly potent and selective nonsteroidal mineralocorticoid receptor
TLDR
(R)-14c was identified as a potent nonsteroidal MR antagonist with higher than 500-fold selectivity versus PR and other related nuclear hormone receptors, with improved solubility as compared to 2 and pharmacokinetic properties suitable for oral administration. Expand
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