John Steele

Reductive alkylation on a solid phase: Synthesis of a piperazinedione combinatorial library

Abstract The synthesis of a prototype trisubstituted piperazinedione combinatorial library of 1,000 compounds has been achieved from three precursor sets — two sets of ten α-amino acids and one set of ten aldehydes. A sodium triacetoxyborohydride-mediated reductive alkylation was crucial to the success of the multi-step synthesis on resin. This protocol represents a new method to augment compound files rapidly with novel heterocyclic entities for high-speed screening.

A mild and selective C-3 reductive alkylation of indoles

In the presence of triethylsilane and trifluoroacetic acid, the reaction between indoles and aldehydes in dichloromethane at 0°C, results in good yields of C-3 reductively alkylated products. The transformation is most effective for the preparation of 3-(arylmethyl)indoles 6 from aromatic aldehydes.

The combinatorial synthesis of a 30,752-compound library: discovery of SAR around the endothelin antagonist, FR-139,317

Abstract A combinatorial library of 30,752 compounds has been synthesised from a set of 32 natural and unnatural amino acids. The library was designed to include the known endothelin antagonist, FR-139,317, as a positive control, and this and a number of close analogues were shown to be the most potent compounds. Thus, combinatorial libraries may be used both to discover leads and rapidly explore SAR. A combinatorial library of 30,752 compounds has been synthesised from a set of 32 natural and unnatural amino acids. The library was designed to include the known endothelin antagonist, FR-139,317, as a positive control, and this and a number of close analogues were shown to be the most potent compounds. Thus, combinatorial libraries may be used both to discover leads and rapidly explore SAR.

Thromboxane modulating agents. 1. Design of 1-[(arylsulfonyl)amino] alkylindole derivatives as dual thromboxane synthase inhibitor/thromboxane receptor antagonists.

Abstract The design of a series of dual thromboxane synthase inhibitor/thromboxane receptor antagonists based on an indole thromboxane synthase inhibitor template is described. The indole-5-propanoic acid derivatives 17, 22 and 23 were found to be potent dual agents in vitro.

Thromboxane modulating agents. 2. Thromboxane receptor antagonists derived from the thromboxane synthase inhibitor dazmegrel.

Abstract The design of dual thromboxane synthase inhibitor/thromboxane receptor antagonists (e.g. 15 ) based on the structure of the thromboxane synthase inhibitor dazmegrel is described. More potent receptor antagonists (e.g. 16c ) result from replacement of the pyridinyl subsituent with 4-fluorophenyl. Modelling suggests the existence of more than one site capable of interacting with the aryl sulfonamide of TxA 2 receptor antagonists.

Thromboxane modulating agents. 4. Design and synthesis of 3-(2-[{(4-chlorophenyl)sulfonyl}-amino]ethyl)benzenepropanoic acid derivatives as potent thromboxane receptor antagonists

The design of a series of thromboxane receptor antagonists based on 3-(2-[[(4-chlorophenyl)sulfonyl]amino]ethyl)benzenepropanoic acid (1) is described. Addition of an arylmethyl group at the 5-position of 1 gave exceptionally potent agents in vitro and in vivo, with 13a (UK-147,535) giving complete blockade of the TxA2 receptor for greater than 12 hours in dogs, following an oral dose of 0.1 mg/kg.

Enantiodifferentiation of dihydropyridine PAF antagonists

Abstract The PAF antagonist activity of a series of enantiomeric dihydropyridines is described. In the first example, 1 , the PAF antagonist activity and calcium channel blocking activity reside in opposite enantiomers. Subsequent examples also display enantioselectivity and the SAR of the series is described.