Statistical analysis of the effects of common chemical substituents on ligand potency.

The results of a statistical analysis of more than 84,000 compounds from lead optimization programs against 30 different protein targets is presented, with a focus on the effects that different chemical substituents have on compound potency. It is observed that the potency changes induced by most chemical groups follows a nearly normal distribution centered near zero (i.e., no effect on potency). However, the widths of the distributions vary significantly between different substituents, and these effects cannot be rationalized by simple physicochemical parameters. In addition, certain substituents consistently bias the distribution toward higher or lower potency, suggesting the existence of preferred and nonpreferred chemical groups for lead optimization. The implications of these results for understanding protein-ligand recognition and for enhancing the efficiency and speed of lead optimization will be discussed.

Construction and validation of an automated flow hydrogenation instrument for application in high-throughput organic chemistry.

This manuscript details the construction of a fully automated flow hydrogenation apparatus for use in high-throughput organic synthesis. The instrument comprises of a Bohdan robot platform coupled with a ThalesNano H-cube hydrogenator and a series of solvent valves and pumping mechanisms. Using this instrument, we have been able to fully automate a number of key transformations that could not otherwise be conveniently undertaken in a high-throughput manner.

Refolding of misfolded mutant GPCR: post-translational pharmacoperone action in vitro.

All reported GnRH receptor mutants (causing human hypogonadotropic hypogonadism) are misfolded proteins that cannot traffic to the plasma membrane. Pharmacoperones correct misfolding and rescue mutants, routing them to the plasma membrane where they regain function. Because pharmacoperones are often peptidomimetic antagonists, these must be removed for receptor function after rescue; in vivo this necessitates pulsatile pharmacoperone administration. As an antecedent to in vivo studies, we determined whether pharmacoperones need to be present at the time of synthesis or whether previously misfolded proteins could be refolded and rescued. Accordingly, we blocked either protein synthesis or intra-cellular transport. Biochemical and morphological studies using 12 mutants and 10 pharmacoperones representing three different chemical classes show that previously synthesized mutant proteins, retained by the quality control system (QCS), are rescued by pharmacoperones, showing that pharmacoperone administration in vivo likely need not consider whether the target protein is being synthesized at the time of drug administration.

Utilization of NMR-derived fragment leads in drug design.

The advent of large-scale NMR-based screening has enabled new strategies for the design of novel, potent inhibitors of therapeutic targets. In particular, fragment-based strategies, in which molecular portions of the final high-affinity ligand are experimentally identified prior to chemical synthesis, have found widespread utility. This chapter will discuss some of the practical considerations for identifying and utilizing these fragment leads in drug design, with special emphasis on some of the lessons learned from more than a decade of industry experience.

Rapid and efficient synthesis of 1,2,4-oxadiazoles utilizing polymer-supported reagents under microwave heating.

1,2,4-Oxadiazoles can be rapidly and efficiently synthesized from a variety of readily available carboxylic acids and amidoximes using either method A or method B. The use of commercially available polymer-supported reagents combined with microwave heating resulted in high yields and purities of the product 1,2,4-oxadiazoles in an expeditious manner. [structure: see text]

Use of polymer-supported Pd reagents for rapid and efficient Suzuki reactions using microwave heating.

A rapid and efficient Suzuki coupling protocol has been developed utilizing polymer-supported palladium catalysts and microwave irradiation. It is also shown that solid-phase extraction of excess boronic acids can be rapidly and conveniently accomplished by utilization of a silica-supported carbonate base. [reaction: see text]

Microwave-assisted synthesis utilizing supported reagents: a rapid and efficient acylation procedure.

[reaction: see text] The application of microwave heating to a polymer-assisted solution-phase (PASP) synthesis technique has been utilized to develop a rapid and efficient protocol for the solution-phase synthesis of amides from either amine or carboxylic acid cores.

Synthesis and SAR of highly potent and selective dopamine D3-receptor antagonists: variations on the 1H-pyrimidin-2-one theme.

In our efforts to further pursue one of the most selective dopamine D(3)-receptor antagonists reported to date, we now describe the synthesis and SAR of novel and highly selective dopamine D(3) antagonists based on a 1H-pyridin-2-one or on a urea scaffold. The most potent compounds exhibited K(i) values toward the D(3) receptor in the nano- to subnanomolar range and high selectivity versus the related D(2) dopamine receptor. Thus, 1H-pyridin-2-one 7b displays oral bioavailability (F=37%) as well as brain penetration (brain plasma ratio 3.7) in rat. Within the urea series, an excellent D(3) versus D(2) selectivity (>100-fold) could be achieved by removal of one NH group (compound 6), although bioavailability (rat) was suboptimal (F<10%). These data significantly enhance our understanding of the D(3) pharmacophore and are expected to lead to novel approaches for the treatment of schizophrenia.

Naphthamidine urokinase plasminogen activator inhibitors with improved pharmacokinetic properties.

A series of non-amide-linked 6-substituted-2-naphthamidine urokinase plasminogen activator (uPA) inhibitors are described. These compounds possess excellent binding activities and selectivities with significantly improved pharmacokinetic profiles versus previously described amide-linked inhibitors.

Elimination of antibacterial activities of non-peptide luteinizing hormone-releasing hormone (LHRH) antagonists derived from erythromycin A.

Antibacterial SAR for a series of macrolides derived from erythromycin A that are potent LHRH antagonists was developed in an attempt to eliminate the antibiotic activities of these compounds. Increasing the size of the alkyl substituents on the desosamine 3'-amine resulted in potent LHRH antagonists that were inactive against staphylococcal bacteria strains, and were significantly (>10-fold) less active against streptococcal bacteria strains. Complete elimination of antibacterial activities could be achieved by replacement of one or both methyl groups on the 3'-amine with a large alkyl substituent.