Edmund J. Moran

Synthesis of tetrasubstituted imidazoles via α-(N-acyl-N-alkylamino)-β-ketoamides on Wang resin

The first example of a four component condensation of arylglyoxals, 1° amines, carboxylic acids and isocyanides on Wang resin is described. These products can be cyclized in the presence of NH4OAcAcOH to yield tetrasubstituted imidazoles.

2,4,5-trisubstituted imidazoles : Novel nontoxic modulators of P-glycoprotein mediated multidrug resistance. Part 1

Solution-phase combinatorial chemistry was applied to the optimization and development of clinical candidate OC144-093 (22), a novel and nontoxic modulator of P-glycoprotein mediated multidrug resistance.

Highly convergent approach to the synthesis of the epoxy-amide fragment of the azinomycins

Abstract An efficient synthesis of the α-acyl amide fragment of the azinomycin antibiotics has been accomplished using the P asserini three-component condensation. Good diastereoselectivity was observed for a variety of isocyanide precursors.

A multivalent approach to the discovery of long-acting β 2- adrenoceptor agonists for the treatment of asthma and COPD

A multivalent approach was applied to the design of long-acting inhaled β(2)-adrenoceptor agonists. A series of dimeric arylethanolamines based on the short acting β(2)-adrenoceptor agonist albuterol were prepared, varying the nature and length of the linker between the basic nitrogens. None of the C(2)-symmetric dimers demonstrated increased potency, however dimer 5j, derived from 4-phenethylamine, was found to have increased binding potency in vitro relative to the parent monomer. Optimization of this structure led to the identification of 22 (milveterol) which demonstrates high potency in vitro and long duration of action in a guinea pig model of bronchoprotection.

Synthetic studies towards carzinophilin : synthesis and ammonium hydroxide-induced rearrangement of the epoxi-acid fragment

Abstract An efficient synthesis of the epoxide-containing fragment 4 of carzinophilin has been completed. Intramolecular acyl transfer of a related epoxide afforded amide 16 . Comparison by 1 H NMR of 4 and 16 with authentic natural product provides further evidence for structural revision of carzinophilin.

Simplified method for the isolation of thermally labile drug-DNA adducts: Characterization of chlorambucil and carzinophilin/azinomycin B alkylation products

Abstract A simple and rapid method has been developed for the isolation of thermally labile DNA alkylation products. Use of calf thymus DNA in combination with size exclusion filtration provides good yields >40% of chlorambucil-guanine adducts. Application of this method to the isolation of alkylation products of carzinophilin/azinomycin B affords material consistent with guanine monoalkylation.

Mono-osmylation of dehydroamino acid dienes: synthesis of dehydroamino acids related to the azinomycins

Abstract Dehydroamino acid dienes 11A-C were synthesized and subjected to the Sharpless asymmetric dihydroxylation, producing diols 13A-C . Diol 13A was further converted to the naphthoate derivative 18 and to the triacetate 19 .

Discovery of TD-4306, a long-acting β2-agonist for the treatment of asthma and COPD.

A multivalent approach focused on amine-based secondary binding groups was applied to the discovery of long-acting inhaled β2-agonists. Addition of amine moieties to the neutral secondary binding group of an existing β2-agonist series was found to provide improved in vivo efficacy, but also led to the formation of biologically active aldehyde metabolites which were viewed as a risk for the development of these compounds. Structural simplification of the scaffold and blocking the site of metabolism to prevent aldehyde formation afforded a potent series of dibasic β2-agonists with improved duration of action relative to their monobasic analogs. Additional optimization led to the discovery of 29 (TD-4306), a potent and selective β2-agonist with potential for once-daily dosing.

Multivalent design of long-acting β(2)-adrenoceptor agonists incorporating biarylamines.

A series of potent β2-adrenoceptor agonists incorporating a biarylamine secondary binding group was identified. The previously reported milveterol (5), identified by a multivalent approach and containing a typical β2-agonist primary binding group linked via a phenethylamine linker to a hydrophilic secondary binding group, served as an initiation point. A more hydrophobic set of secondary binding groups was explored, prepared rapidly from a common intermediate by Buchwald-Hartwig amination. TD-5471 (25), a potent and selective full agonist of the human β2-adrenoceptor, was identified as the most promising agent. It is potent, with slow onset in an in vitro guinea pig trachea model and shows a dose-dependent and long duration of action in an in vivo guinea pig model of bronchoprotection. TD-5471 is structurally differentiated from milveterol and its long duration of action is consistent with a correlation with hydrophobicity observed in other long-acting β2-agonist discovery programs.