Andrew David Morley

Diamine containing VLA-4 antagonists

Design and synthesis of a library as potential VLA-4 antagonists has been accomplished, based around a proposed pharmacophoric model. Compounds possessing submicromolar potency were identified and structure-activity relationships were seen across the library. Further derivatisation produced compounds with IC(50)s <10 nmol for inhibiting the VLA-4 mediated binding of fibronectin to RAMOS cells, providing an ideal starting point for a lead optimisation Programme.

Synthesis of N-alkoxybenzimidazoles and N-alkoxypyrimidazoles

A variety of novel N-alkoxy aromatic-fused imidazoles have been prepared in a simple two-step process from 2-fluoro nitroaromatics and 2-chloro-3-nitropyridine. The imidazole forming step involves tandem heterocyclisation and O-alkylation with an in situ alkylating agent, and supports prior mechanistic proposals. Additional mechanistic experiments are described. The protocol is versatile with respect to both substrate halo-nitro aromatics and to the nature of the added electrophile (halides) used in the second step, and thereby significantly extends the scope of this reaction and its applicability to diverse synthesis. This methodology can also be used to generate various types of novel N-alkoxypyrimidazoles (4-deazapurine analogues), and an X-ray structure of one such pyrimidazole is presented

Optimisation and synthesis of libraries derived from phenolic amino acid scaffolds

Abstract Functionalisation of a series of resin bound phenolic amino acids is described, employing Irori technology to produce multidimensional libraries.

Allyloxycarbonyl—a useful protecting group for phenolic amino acids and applications on solid support

Abstract Bis-protection of phenolic amino acids can be achieved in a one-pot procedure using allyl chloroformate. Subsequent immobilisation via the free acid onto solid support then permits the carbonate protecting group to be selectively removed under mild conditions.

Synthesis of novel 2,2- and 1,1-linked dimeric ‘head-to-head’ N-alkoxybenzimidazoles

Abstract Synthesis of two new types of ‘head-to-head’ N , N -alkoxy bisbenzimidazoles is described. The proposed intermediate N -oxy benzimidazole from base-induced heterocyclization of N -alkylnitroanilines can be trapped with a biselectrophile (to give an N , N -linked dimer), or double heterocyclization of dimeric nitroanilines can be intercepted by electrophile trapping of both N -oxybenzimidazole termini to give C2,C2-linked dimers. These represent two regioisomeric motifs constituting new classes of benzimidazole dimers.