Development candidate

Development candidates must be measured against multiple performance criteria, including such aspects as potency, safety, and novelty. Conflict may be experienced between the criteria, in which improved performance in one criterion can only be achieved at the expense of detriment to another. In this situation—as is often the case for activity against bioavailability—a trade-off is said to exist between the objectives. A trade-off between potency and safety may also be present. 

One of the first decisions that must be made relative to a field residue program is the scope of the overall project. A program for a new development candidate will be... 

Abstract High quality leads provide the foundation for the discovery of successful clinical development candidates, and therefore the identification of leads is an essential part of drug discovery. Many factors contribute to the quality of a lead, including biological, physicochemical, ADME, and PK parameters. The identification of high quality leads, which are needed for successful lead optimization, requires the optimization of all of these parameters. Parallel optimization of all parameters is the most efficient way to achieve the goal of lead identification. 

The development of maraviroc (21), much like other chemokine receptor antagonists, started with a high-throughput screen employing a competition binding assay and led to the hit compound UK-107,543. Chemical optimization of this compound led to the development candidate UK-427,857 during this optimization phase, a parallel characterization of the compounds was performed... 

The discovery process for all of these development candidates was similar. Antagonists exhibiting low nanomolar affinities were discovered through competition binding assays, and the antagonists were able to inhibit receptor func-... 

Efavirenz , a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), and a Previous Structurally Related Development Candidate... 

Efavirenz (1) is the second NNRTI development candidate at Merck. Prior to the development of 1, we worked on the preparation of the first NNRTI development candidate 2 [2]. During synthetic studies on 2, we discovered and optimized an unprecedented asymmetric addition of an acetylide to a carbon-nitrogen double bond. The novel asymmetric addition method for the preparation of 2 also provided the foundation for the process development of Efavirenz . Therefore, in this chapter we will first discuss chemistries for the preparation of 2 in two parts process development of large scale synthesis of 2 and new chemistries. Then, we will move into process development and its chemistries on Efavirenz . 

NNRTI and a Previous Structurally Related Development Candidate... 

The original Medicinal Chemistry route was straightforward but, from a process chemistry point of view [20], several problems were identified at the beginning of the project and some of them were quite similar to those for the previous development candidate ... 

Compound 1 was the first cyclopentane-based NK-1 receptor antagonist development candidate at Merck. It contains five stereocenters a central core possessing three contiguous all-trans stereocenters, a pendent bis(trifluoromethyl)-benzyHc ether, and a nipecotic acid moiety (Figure 7.1). Key to the successful preparation of 1 was construction of the trans, trans-cyclopentyl core and installation of the unsymmetrical secondary-secondary (sec-sec) ether. The preparation of 1 is the focus of this chapter. 

Lee CP, RLA Devrueh, PL Smith. (1997). Selection of development candidates based on in vitro permeability measurements. Adv Drug Delivery Rev 23 47-62. 

Two papers described the optimization of LLE and physicochemical properties in a series of pyrazole HTV nonnucleoside reverse transcriptase inhibitors (NNRTIs) and the selection of lersivirine (6) as a development candidate [15,16]. The early lead (7) was relatively lipophilic (clogP = 4.3), rapidly metabolized in human liver microsomes and had an LLE of only 1.9 [pIC50 (HIV RT) - clogP] [15]. An optimization program targeting increased LLE in less lipophilic compounds of low MW (to... 

Optimization of the large (MW = 512), lipophilic (clogP = 7.6), and very potent (Kj = 0.22 nM) Vascular Endothelial Growth Factor Receptor Tyrosine Kinase (VEGFR TK) inhibitor 8 (LLE = 2.1) to produce the development candidate axitinib (9) was recently reported [17]. 

Examples of the application of strategies based on increasing LLE or LipE and optimizing physicochemical properties as key components of medicinal chemistry programs that delivered clinical development candidates have begun to be described in the last year or so. It remains to be seen whether the hoped for reduction in compound attrition that this approach seeks to achieve will be realized, as it is early days. 

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