Medicinal chemistry programs

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. 

When the medicinal chemistry program began in late 1999, nearly all of the DPP-4 inhibitors known in the literature were derived from a-amino acids, and those lacking an electrophile such as the isoleucyl thiazolidides were considerably less potent than those containing a nitrile or boronic acid such as DPP728. One report suggested that cyclohexylglycine derived inhibitors showed improved potency... 

To develop safer drugs, it is important to identify irreversible CYP inhibitors at an early stage in the drug discovery process. Certain substructures, reviewed in this chapter, are frequently responsible for irreversible CYP inhibition and either their use in medicinal chemistry programs should be limited or their potential for irreversible binding to CYPs should be carefully monitored. 

Starting with the known thrombin inhibitors Argatroban and Afx(2-naphthyl-sulfonyl-glycyl)-DL-/>-amidinophenylalanyl-piperidine (NAPAP), a group at Roche initiated a medicinal chemistry program to develop thrombin inhibitors with reduced toxicity and an improved hemodynamic profile [17]. 

Cosmeceuticals are substances that are applied to skin or hair but do not modify its structure and function. One aspect that differentiates cosmeceuticals from cosmetics is that most, if not all, of them originate from bona fide medicinal chemistry programs. In this chapter, four representative cosmeceuticals are discussed isotretinoin (1) and tazarotene (2) for acne and minoxidil (3) and finasteride (4) for hair growth, respectively. Ironically, in spite of their market successes, neither minoxidil nor... 

In addition, the conversion of a compound collection of drug-like heterocycles as might be used in a medicinal chemistry program was investigated. An equimolar mixture of 20 pyrazole acids, synthesized by a split-and-mix approach, was treated with methyl resin 10 (Ri = CH3, 5 equiv.) for 6 h to yield the respective pyrazole esters. All 20 pyrazole acids in the starting reaction mixture and all their corresponding 20 pyrazole methyl esters in the product mixture could be identified by FT-ICR MS coupled to micro-HPLC with a relative mass error <2.2 ppm. 

In a medicinal chemistry program aiming to discover p38 MAP kinase inhibitors, the group of Skjaerbaeck introduced microwaves in order to achieve aryl decoration of the aniline backbone [81]. A systematic optimization of the catalyst, solvent, base and reaction time/temperature delivered a general procedure for the expeditious production of the desired aryl aminobenzophe-nones within 3-15 minutes, as demonstrated in Scheme 23. 

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