Developmental candidate

Efavirenz (1) was chosen over compound 2 as a developmental candidate in 1993 based on its better antivirus activities, especially against resistant strains [1, 17]. Efavirenz is the first HIV non-nucleoside reverse transcriptase inhibitor (NNRTI) which was approved by the FDA on September 21, 1998. The original Medicinal Chemistry method to prepare Efavirenz is depicted in Scheme 1.14. 

BAY X 8843 36 appeared to be a useful developmental candidate due to its powerful in vitro and in vivo activity and insignificant neurotoxicity [113]. Preclinical development was abandoned however due to the toxicological effects obtained in monkeys. 

In addition to BAY X 8843 36, its 8-chlorine analogue 8-chloro-l-cyclopropyl-7-(S,S-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarbo-xylic acid hydrochloride BAY Y 3118 45 was also an important developmental candidate. Due to its broad activity spectrum, which included anaerobic bacteria [129-136], it had the potential for becoming a problem-solver . Unfortunately, during the Phase I trials photo toxic side effects occurred [137] which were due to the chlorine substituent in the 8-position, and these led to an abandonment of the development of this compound. 

Marketing to continue evaluating the status of competitor s drug candidates and the potential of the developmental candidate to fill a medical need and to prepare for product launch... 

This section describes some of the biological research experiments that could, and in most cases should, be conducted to evaluate the potential of a lead compound to become a developmental candidate. Figure 3 shows where these developability experiments fit into the drug discovery and development process. These nondefinitive developability studies may also uncover problems that have to be resolved before the definitive preclinical development studies required to support an IND submission are started and before the clinical protocols to evaluate the safety and efficacy of the drug candidate in humans are designed. 

The combinatorial decoration or derivatization of existing natural products is a popular method for library creation. Among targets for such exercises are the alkaloids yohimbine and scopolamine, terpenoids and steroids, and the heterocyclic peptide antibiotic GE-2270A (Figure 11). In the latter case, combinatorial variation was instrumental in the discovery of a developmental candidate now in clinical trials at Vicuron. Pfizer, the world s largest pharmaceutical company, recently acquired Vicuron for the sum of 1.9 billion, a mark of approval for natural product-based combinatorial chemistry. 

Figure 3. Three-step process for the identification of a developmental candidate.

Balbach S and Korn C. Pharmaceutical Evaluation of Early Developmental Candidates The 100 mg Approach. IntJ Pharm 2004 275 1-12. 

At that time about ten compounds of this structural class were developmental candidates or had been introduced into the market. Of these carboxin (1) and oxy-carboxin (2) (Table 13.3.1 below) are well known examples that are still used today [2],... 

Absence from the first developmental stages as in whales and some Old World monkeys suggests that functional substitution is provided by other nasal chemoreceptors. The ganglia and fibres of the terminal nerve system (N. terminalis, Fig. 2.9) are the principal candidate (Wirsig and Leonard, 1987). The role of the trigeminal input, although a minor sensor, could well be expanded in a limited capacity (Tucker, 1971 Wysocki and Meredith, 1987 Westhofen, 1987). 

Representation requires that the designer of a typical evolutionary computation algorithm (EA) formulates one inadaptable blueprint for the solution of some problem, then present the variables of that blueprint in a form that is amenable to manipulation by the genetic operators of the EA. Fitness evaluation, on the other hand, has limited GA in two distinct ways (1) it has limited environmental feedback to the confines of a formula or algorithm, which reflects accurately and exclusively the quality of the complete candidate solution from the perspective of the human designer. In addition, (2) fitness evaluation has proven to be the most computationally costly part of a typical EA. Note that elaborate developmental mappings actually increase that computational cost. However, our interest here lies in the limiting effects of representation. 

Many studies, particularly in the life sciences area, are not reproducible because small quantities of unique materials were used in the research. A commitment was made when the present program began to characterize fully the elastomers utilized in the development of accelerated fatigue tests. At the start of the program, a limited number of candidate materials was selected to be obtained in quantity, characterized, and used for all of the developmental testing. 

Miura, T. and R.M. Takahashi. 1974. Insect developmental inhibitors. Effects of candidate mosquito control agents on nontarget aquatic organisms. Environ. Entomol. 3 631-636. 

When a prospective drug under development for use in women of childbearing potential is determined to cause developmental toxicity in laboratory animals, the first question to be considered is whether that agent would cause developmental toxicity in humans at the anticipated therapeutic dosage level. This assessment and the related decision of whether to continue development of the drug candidate are currently based on the following... 

A prescreen to select among possible backups to a lead drug candidate that had been found to be developmentally toxic. 

The metabolites of a drug candidate are usually characterized after the drug candidate has entered into the developmental stage. However,... 

Figure 7 shows the effect of ectopic administration of T3 to the developing zebrafish embryo. At nontoxic concentration (50 nM), only a moderate fraction (less than 5%) of the zebrafish transcriptome shows significant changes. Ossification, visual processes, and the hematopoietic system were the physiological processes most affected by the treatment, in a pattern consistent with an advancement of the development in these particular functions (Fig. 7b). Genes involved in these three processes are known targets for TDCs during metamorphosis in amphibians, teleost fishes, and lampreys [54—60], and constitute molecular counterparts of different endpoints used to test for TDC in amphibians [56, 58]. Therefore, they are excellent candidates for markers of thyroid disruptors in zebrafish at early developmental stages. Chapter 14 provides a more in-deep description of the developmental effects of thyroid disruption in zebrafish embryos.

Where functional cross-reactivity to at least one of the usual toxicology species is present, and appropriate assays for PK and PD have been developed, the clinical candidate can be used in a relatively conventional developmental toxicity program with that species (preferably the rat, for which the most background data will be available). Following early sub-chronic repeat-dose toxicity testing in the rodent (usually up to 1 month s duration), with accompanying PK/PD data, the reproductive study program can be planned as appropriate to the circumstances. 

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