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1.
ACS Med Chem Lett ; 5(1): 78-83, 2014 Jan 09.
Article in English | MEDLINE | ID: mdl-24900776

ABSTRACT

The in silico construction of a PDGFRß kinase homology model and ensuing medicinal chemistry guided by molecular modeling, led to the identification of potent, small molecule inhibitors of PDGFR. Subsequent exploration of structure-activity relationships (SAR) led to the incorporation of a constrained secondary amine to enhance selectivity. Further refinements led to the integration of a fluorine substituted piperidine, which resulted in significant reduction of P-glycoprotein (Pgp) mediated efflux and improved bioavailability. Compound 28 displayed oral exposure in rodents and had a pronounced effect in a pharmacokinetic-pharmacodynamic (PKPD) assay.

4.
Proc Natl Acad Sci U S A ; 99(3): 1270-3, 2002 Feb 05.
Article in English | MEDLINE | ID: mdl-11818565

ABSTRACT

Combinatorial small molecule growth algorithm was used to design inhibitors for human carbonic anhydrase II. Two enantiomeric candidate molecules were predicted to bind with high potency (with R isomer binding stronger than S), but in two distinct conformations. The experiments verified that computational predictions concerning the binding affinities and the binding modes were correct for both isomers. The designed R isomer is the best-known inhibitor (K(d) approximately 30 pM) of human carbonic anhydrase II.


Subject(s)
Carbonic Anhydrase II/chemistry , Algorithms , Amino Acid Sequence , Carbonic Anhydrase II/metabolism , Combinatorial Chemistry Techniques/methods , Humans , Ligands , Microchemistry/methods , Models, Molecular , Protein Conformation
6.
Angew Chem Int Ed Engl ; 40(20): 3892-3894, 2001 Oct 15.
Article in English | MEDLINE | ID: mdl-29712155

ABSTRACT

Remarkable selectivity is exhibited in the photooxidation of 20-methoxychlorin methyl ester (1) to exclusively yield the C1-C20 bond cleaved product 2. This selectivity lends strong support to the hypothesis that a hydroxy or equivalent group at C20 directs the C1-C20 bond cleavage that transforms chlorophylls into krill and dinoflagellate luciferins.

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