Robert K. Baker

Piperidine-ether based hNK1 antagonists 2: Investigation of the effect of N-substitution

Abstract The effect of nitrogen substitution on the binding affinity of the piperidine-ether substance P antagonist L-733,060 for the hNK 1 receptor and L-type Ca 2+ channel is discussed.

3-benzyloxy-2-phenylpiperidine NK1 antagonists: The influence of alpha methyl substitution

Abstract In vitro metabolism studies on a series of 3,5-bis(trifluoromethyl)benzyl ethers have identified 3,5-bis(trifluoromethyl)benzoic acid as a significant metabolite possibly arising via oxidation of the benzylic position. A methyl group was introduced in an effort to suppress this route of metabolism. One diastereoisomer displayed an increase in affinity and a marked improvement in duration of action. In vitro metabolism studies on a series of 3,5-bis(trifluoromethyl)benzyl ethers have identified 3,5-bis(trifluoromethyl)benzoic acid as a significant metabolite possibly arising via oxidation at the benzylic position. A methyl group was introduced in an effort to suppress this route of metabolism. One diastereoisomer displayed an increase in affinity and a marked improvement in duration of action

Quinuclidine based NK-1 antagonists 2: determination of the absolute stereochemical requirements

Abstract The relative and absolute stereochemical requirements for high affinity binding to the human NK-1 receptor are defined for a series of quinuclidine ethers. Whilst the S stereochemistry at C-3 is essential for high afifnity, surprising both epimers at C-2 are active.

Phenyl-glycinol based NK1 receptor antagonists — towards the minimum pharmacophore

The effects of alternative benzyl ether substitution and the introduction of steric constraints on the binding affinity for the hNK1 receptor of a phenylglycinol based Substance P antagonist is described.

Synthetic studies on the immunosuppressive agent FK-506: Enantioselective synthesis of a C22C34 fragment

Abstract The C28C32 cyclohexyl group of the natural product, FK-506, was prepared enantioselectively from the iodolactone by replacement of iodide with retention of configuration . The C27C28 trisubstituted olefin was introduced stereoselectively via a classical aldol/elimination sequence employing titanium enolate methodology. Elaboration of this chemistry has led to a synthesis of a C22C34 fragment of the natural product.

Inhibitors of myo-inositol monophosphatase unrelated to the enzyme substrate

Abstract Hydroxymethylenebisphosphonate derivatives have been found to be competitive inhibitors of myo-inositol monophosphatase.

Synthetic studies on the immunosuppressive agent FK-506: Construction of the polycarbonyl region

Abstract The C10C17 fragment of the natural product, FK-506, has been stereoselectively synthesized from L-gulose. Methods for elaboration to the C1C17 fragment and installation of the C9 carbonyl group are described.