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Medicinal Chemistry is the design and invention of novel small molecule therapeutics. Process research optimization and scale-up transition from the early stage of medicinal chemistry candidate selection to clinical trial and commercial manufacturing.
- Invention of novel pharmacophores and scaffolds
- Expansion of analog series
- Hit generation
- Lead generation
- Patentability and freedom operate analyses
- Screening druggability to guide lead optimization (potency, bioavailability, safety, efficacy)
- Scale-up research to optimize cost, ease of synthesis, avoidance of conflicting intellectual property
- Process optimization to 50 L reactor volume in mini-pilot facility
- Transition to pilot facility in 1000 L reactor volume
- Migration to industrial level production, up to 10,000 L
Led by Dr. Prakash Jagtap, Ph.D., Vice-President of Chemistry
Dr. Jagtap is a veteran medicinal chemist with 30 years of experience and has played leading roles at several biotechnology and pharmaceutical firms resulting in the advancement of his patented technologies to the clinical stage of development.
General Synthetic Considerations
The synthetic schemes and procedures provided by the client will be evaluated, where available, and compared to literature methods. In many cases, it is necessary to find alternate synthetic routes rather than employ the synthetic scheme provided by clients. Where possible, we also look for synthetic routes that have late common intermediates that will give access to a large set of desired compounds. This approach can be exploited for subsets in earlier rounds of synthesis wherein a given part of the molecule is being examined, but may or may not be as applicable in later iterations where the chemistry is more focused and critical and very specific molecules need to be prepared.
In the phase of early structure activity relationship (SAR), there is more flexibility in the choice of compounds to make. Testing the effects of substituents at site “A” on a molecule can be performed with readily available and inexpensive reagents. Later, as the SAR is better understood, the compounds to be made become more specific and particular hypotheses are to be tested (e.g., the substituent at site A now has to be X-Y-Z).
As the information in the SAR increases and appears to be pointing in a certain direction, the synthetic routes need to be reassessed periodically, not just to provide the immediate compounds, but also to anticipate scale up for further testing, toxicology testing, and ultimately clinical trials. The yields, number of synthetic steps, safety, and practical route of synthesis are a critical factor in the decision to advance optimized to candidate status. It is unlikely that serious investment of time and money will be dedicated into process-research for a potential drug candidate until it is the clinical candidate. Even so, anticipation of the requirements of the synthetic needs can influence the choice of the clinical candidates. The timing for initiation of process scale-up research is a business decision to be made at a later stage, but will be influenced by the chemistry to date.
As lead optimization work progresses, factors that may indirectly effect the SAR should be considered. For acids and bases, the choice between preparing salts or the free base for the testing, and which salts (sodium, potassium, solubility, dissolution and stability are key factors in this decision). The resulting pH of solutions is important for concentrated dosing solutions, and if buffers are to be used, then what about tonicity? These are practical issues to be resolved by the chemists and biologists and are aided by a close working relationship. As a part of preformulation, SG focuses on the solubility of lead compounds and performs salt screening experiments on the selected lead molecules that carry basic polar groups.
Salzman Group also carries out the synthesis of pro-drugs if necessary. This is a useful way to ascribe certain characteristics to a molecule to increase bioavailability; for example, while generating an active drug in vivo, usually after enzymatic cleavage. Pro-drugs can be used to modify the PK and ADME characteristics of a drug as well as its bioavailability via various routes.
In cases where two different leads or hits have been identified, they should be treated as having unrelated SARs, unless there is sufficient structural similarity to suggest otherwise. Even if the latter is true, the dominant pharmacophore in each case should be identified (as described below). Molecular docking experiments may suggest common or similar binding motifs (not necessarily the principal pharmacophore) or even whether the leads are binding (if ligands) to the same area of the protein or binding site.
Identification of Pharmacophores
In lead optimization projects, the early SAR study or any in vitro data obtained for an early hit and its derivatives are very crucial in planning. If there are a significant amount of data, then they usually reveal which functional groups or which part of the molecule is contributing towards the activity or may be detrimental to the activity. It also offers insight regarding the red flags about the molecule or the scaffold from which the molecule was derived. This information is best obtained by talking to the Sponsor’s scientists who worked on the projects. This helps us to avoid the unnecessary duplications of the experiments that were not successful.
If there is no prior SAR (for instance, with a “hit” from a non-targeted screened library), it is helpful to perform an initial round synthesis and activity testing to identify the pharmacophores responsible for activity. With weak hits, inhibitory activity may involve non-specific binding that does not lend itself to improved potency. These experiments are for informational purposes to determine the core structure required for activity and identify which sites on the core structure are sensitive to substitutions or modification and those that are not.
A carefully planned and iterative style of activity testing of synthesized samples can rapidly identify the pharmacophores responsible for activity in that assay. The design of the experiment to identify the assay-sensitive sites can include removing substituents from rings, introducing or removing heteroatoms from rings, varying the length and nature of linking chains, or switching ring systems. Broad changes are particularly useful for exploring a “hit” with weak activity from a non-targeted screening assay, where no similar structures were tested.
The compounds synthesized will be screened for their activity in an in vitro assay against the target to facilitate the initial SAR determination of the active pharmacophore. A description of the approach to the screening evaluations is provided further below for in vitro assessments.
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