The rational drug design for antimalarial was reported. Using the 4-aminoquinoline amodiaquine as a template, they designed analogues that are highly effective against chloroquine-resistant parasites and against parasites obtained from clinical failures after treatment with amodiaquine. At first, they exchanged hydroxyl and diethylaminomethyl of amodiaquine to avoid quinoneimine bioactivation. The resulting compound 3 was subject to unacceptably high first pass metabolism to dealkylated metabolites in four animal species. After optimization of compound 3, N-tert-butyl isoquine (GSK369796) was discovered.
Recent changes in the Food and Drug Administration’s guidance on metabolites in safety testing (MIST) have had a major impact on the approach to toxicity testing of drug metabolites. These changes have required new strategies for the evaluation of metabolites at the early stages of drug development. In this issue, toxicologists from industry and academia share their experiences and insights from several years of efforts to meet the challenge of this new paradigm.
To generate new scaffolds that could potentially displace the dipeptide valine-proline motif, the software program CAVEAT was utilized. CAVEAT databases of minimized compounds from commercially available small molecules were constructed and searched. Genentech's chemists selected an azabicyclooctane as a synthetically accessible, conformationally constricted unique template. The synthetic strategy of azabicyclooctanes 4, and 5 is noteworthy. On the basis of Corey lactone's synthesis, treatment of gamma, delta-unsaturated amine 2 with iodine gave a bicyclic compound 3 through an iodonium intermediate. Azides 6 and 7 from iodine 3 were separable on silica gel, and yield of each isomer was about 30%. Hydrogenation of the azide 7 provided the amine 5. In this scheme, gram scale synthesis of azabicyclo-intermediates 4 and 5 can be achieved. I think this template is an useful substructure as medicinal chemistry. The optimized compound 14b had 10-15-hold more potency than a flexible referred compound 15b, thus conformational constriction worked.
Pharmacia's CETP inhibitor, compound 13 has highly potent, but modest oral exposure and in vivo efficacy. Such poor PK might result from the quite flexibility (12 rotatable bonds) of this compound. Hence, J&J's chemists designed conformationally constrained compounds to improve PK profile. Designed compound 13B displayed acceptable potency (400 nM) as a new scaffold. Lead optimization gave compound 12, which showed good potency (45 nM), and acceptable PK (rats: 31%, dogs:5%, monkeys: 27%). The low distribution of compound 12 may be favorable because CETP is present in plasma. This compound was orally efficacious in vivo. Notable synthetic strategies are 1) palladium-catalyzed acylation of acylchloride with organo-stannane; 2) a copper mediated intramolecular amination of Nosylamine by Fukuyama's method; and 3) N-alkylation with 1,1,1-trifluoro-2,3-epoxypropane and Yb(OTf)3.
The starting lead 2a has an aniline structure, which sometimes exert the potential risk for mutagenecity. This report showed removing this aniline, and improved the potency based on crystal structure analysis. The optimized compound 27e exhibited a glucose-lowering effect after 10 mg / kg oral administration. The structure is similar to the previous reported compound by AstraZeneca.