Current Medicinal Chemistry, 2003, 10, 51-80 51 0929-8673/02 $41.00+.00 © 2003 Bentham Science Publishers Ltd. “Multi-component Reactions : Emerging Chemistry in Drug Discovery” ‘From Xylocain to Crixivan’ Christopher Hulme * and Vijay Gore Department of Small Molecule Drug Discovery, AMGEN Inc., One AMGEN Center Drive, Thousand Oaks, CA 91320, USA Abstract: With the recent emergence of combinatorial chemistry and high-speed parallel synthesis for drug discovery applications, the multi-component reaction (MCR) has seen a resurgence of interest. Easily automated one-pot reactions, such as the Ugi and Passerini reactions, are powerful tools for producing diverse arrays of compounds, often in one step and high yield. Despite this synthetic potential, the Ugi reaction is limited by producing products that are flexible and peptide-like, often being classified as ‘non drug-like’. This review details developments of new, highly atom-economic MCR derived chemical methods, which enable the fast and efficient production of chemical libraries comprised of a variety of biologically relevant templates. Representative examples will also be given demonstrating the successful impact of MCR combinatorial methods at different stages of the lead discovery, lead optimization and pre-clinical process development arenas. This will include applications spanning biological tools, natural products and natural product-like diversity, traditional small molecule and ‘biotech’ therapeutics respectively. In particular, this review will focus on applications of isocyanide based MCR (IMCR) reactions. INTRODUCTION The year 1959 witnessed the discovery of a remarkable four component reaction by Professor Ivar Ugi [1]. A short time later the first medicinal chemistry related application of the U-4CR (Ugi four component reaction) was realized, with the one step preparation of the local anesthetic Xylocain [2]. With tremendous foresight, Ugi also recognized that the reaction was ideally suited to probe structure-activity relationships via the synthesis of ‘large collections of compounds’, now referred to as libraries [3]. Today, with the emergence of combinatorial chemistry and high-speed parallel synthesis, the multi-component reaction (MCR) is widely employed for the rapid assembly of arrays with high molecular diversity [4]. Coupled with a post-condensation modification, the power of these reactions is increased even further, giving rise to a plethora of complex, pharmacologically relevant templates for screening purposes. Simply put, multi-component reactions are synthetically useful reactions in which three or more starting reagents combine in a single event to give a single product that contains features of all the inputs. Early examples of heterocyclic forming reactions include the Hantzsch pyrrole [5], Biginelli [6] and Bucherer-bergs [7] reactions which lie outside the scope of this current review. The advantage of an MCR synthesis over an equivalent linear synthesis is clear, in that the size of a linear derived library is a function of the number of steps and individual inputs. For example, a three *Address correspondence to this author at the Department of Small Molecule Drug Discovery, AMGEN Inc., One AMGEN Center Drive, Thousand Oaks, CA 91320, USA; Tel: 805-447-6493; Fax: 805-480-1346; Email: chulme@amgen.com step synthesis with 10 inputs at each step would have a size of 10 3 compounds, whereas a three component MCR with 10 inputs/component would have the same size, yet be achieved in a single chemical operation [8]. This efficiency is the major driving force behind the recent upsurge in MCR research and examination of recent literature clearly shows a dramatic increase in the number of publications/year on MCR’s [9]. Additional advantages of this methodology are evident when applied to the drug discovery process in general. Before describing these, it seems apt to initially explain the different applications of parallel synthesis in drug discovery. Typically, new hits are identified by screening corporate collections (>300,000 cpds) that consist of compounds from prior in-house programs, commercially acquired compounds or compounds derived from the efforts of an internal combinatorial chemistry group. Going one-step further, combinatorial chemistry derived libraries may be split into three categories: 1) General libraries, specifically designed to fill diversity voids in corporate collections (typically in the 10 3 – 10 4 compound range). In the past few years, combinatorial methods have been extended to the preparation of diverse arrays of complex natural product-like libraries, pivotal in the recently introduced concept of ‘chemical genomics’[10]. 2) Gene family targeted libraries using privileged chemical motifs [11] or public domain structures often seen in ligands that bind to several member targets of the gene family (typically 10 2 – 10 3 compound range). 3) A focused library designed for a specific target and SAR driven (10 – 10 3 compound range).