Sangsoo Kim

Discovery of LB30057, a benzamidrazone-based selective oral thrombin inhibitor

Systematic variation of the so-called P-pocket moiety of benzamidrazone-based selective thrombin inhibitors led to the discovery of LB30057. It is potent (Ki = 0.38 nM for human thrombin), selective (Ki = 3290 nM for bovine trypsin), and orally bioavailable (58% oral bioavailability in dogs). LB30057 was efficacious in thrombosis animal models.

STRUCTURAL MODIFICATION OF AN ORALLY ACTIVE THROMBIN INHIBITOR, LB30057: REPLACEMENT OF THE D-POCKET-BINDING NAPHTHYL MOIETY

An amidrazonophenylalanine derivative LB30057 (2) was identified as a potent (Ki = 0.38 nM), selective, and orally active thrombin inhibitor. As a continuation of studies into benzamidrazone-based thrombin inhibitors, we have structurally modified compound 2 by replacing the naphthyl group with a variety of hydrophobic moieties. This study led to discovery of several compounds with significantly enhanced potency in thrombin inhibition without sacrificing selectivity against trypsin and oral absorption. The highest activity was obtained with compound 23 (Ki = 0.045 nM).

Rational design of selective thrombin inhibitors

Abstract Thrombin inhibitors with functionalized benzamidines as surrogates for arginine were designed, synthesized, and characterized. Amino acid sequence difference in the position 190 between thrombin and trypsin was exploited in the design to enhance selectivity over trypsin. A representative compound 6 showed high potency (Ki of 45.5 nM) and extremely high specificity over trypsin (over 10,000 fold).

Benzylamine-based selective and orally bioavailable inhibitors of thrombin

A series of p-aminomethylphenylalanine derivatives were investigated as novel thrombin inhibitors. This study led to potent inhibitors of thrombin (Ki up to 3.3 nM) that are trypsin-selective, highly orally bioavailable in rats, and highly permeable across Caco-2 cells. The P1 benzylamine binding mode in the thrombin active site was identified by X-ray crystallographic analysis.

Synthesis and structure of ternary molybdenum oxides MMo8O10 (M = Li or Zn) having orthogonal nonintersecting octahedral cluster chains☆☆☆

Abstract The new compounds LiMo 8 O 10 ( I ) and ZnMo 8 O 10 ( II ) have been prepared via reactions in sealed Motubes at 1370–1450°C between Li 2 MoO 4 , MoO 3 , and Mo (3:16:29 mole ratio), and ZnO, MoO 3 , and Mo (1:3:5 mole ratio), respectively. The isomorphous compounds are tetragonal, space group I 4 1 md , Z = 4, with lattice constants a = 5.8515(6) A, c = 24.783(3)A for I , and a = 5.8961(4) A, c = 24.840(3)A for II , as determined from Guinier X-ray powder patterns. Single crystal structure determination shows that these compounds are constructed from infinite chains consisting of edge-shared octahedral cluster units. The structure can be viewed as a stacking along the c axis of layers consisting of parallel chains, with the chains in successive layers oriented alternately along the a and b axes. Intra- and interlayer crosslinking of the chains by MoOMo bonds is represented in the connective formula [( Mo 2 Mo 4 2 O 6 2 O 4 3 ) O 2 3 ] for the octahedral cluster subunits. MoMo bonding within the subunits is strong, but very irregular compared to analogous compounds containing such chains. Subunit MoMo bond order sums indicate that the bond distortions are effective in accommodating a higher electron count in metal-metal bonding states. It is shown that the structures are related to the spinel and rock salt structures through an ordered-defect arrangement of the Mo and O atoms.

A new type of carboxypeptidase A inhibitor: design, synthesis, and mechanistic implication

2-Benzyl-3,4-epoxybutanoic acid (BEBA) which was designed rationally as an irreversible inhibitor of carboxypeptidase A on the basis of the known topology of the active site and catalytic mechanism of the enzyme indeed inactivated the enzyme very efficiently with a covalent modification at the carboxylate of Glu-270. The partition ratio of BEBA was determined to be 20.3. Of four stereoisomers of BEBA, (2S, 3R)and (2R, 3S)-BEBA show the inhibitory activity, and the other two isomers are essentially inactive. This stemspecificity of BEBA in the inhibition was explained with a proposition of a three-dimensional representation of the active site of the enzyme. All four stereoisomers were synthesized effectively and conveniently starting with optically active 2-benzyl-2-vinylacetic acid which was obtained by a kinetic resolution of racemic methyl ester of the acid using a-chymotrypsin. INTRODUCTION Carboxypeptidase A (CPA, EC 3.4.17.1) is a much studied and well characterized metalloprotease, and thus serving as a prototypic enzyme for many metalloenzymes including physiologically important proteases such as angiotensin converting enzyme and enkephalinase (ref. 1,2). The structure of the native enzyme has been determined by X-ray crystallographic method to a resolution of 1.54 A. It preferentially cleaves off the C-terminal amino acid residue that possesses an aromatic side chain from peptide substrate with L-stereospecificity (ref. 1,2). CPA has also served as a model in the development of inhibitor design strategies that can be translated to other metalloproteases of great medicinal importance (ref. 3), and accordingly a good variety of different types and potencies of inhibitors have been developed, culminating to obtaining an inhibitor of a y value in the range of ferntomolar (ref. 4). In this report, we describe the synthesis and mechanistic implication of a new type (pseudomechanism-based 72 1

endo-σ-Bonded group 14 heterodicarboranes: synthesis of [Ph3MC2B9H11]–[M = germanium(IV), tin(IV)] and structure of [10-endo-(SnPh3)-10-µ-H-7,8-nido-C2B9H10][trans-Ir(CO)(PPh3)2(MeCN)]

Reaction of equimolar amounts of thallium(I) salts of monoanionic group 14 heterodicarboranes [Ph3MC2B9H11]–, generated in situ by treating Tl2C2B9H11 with Ph3MCl in MeCN, and trans-Ir(CO)(PPh3)2Cl afforded [10-endo-(MPh3)-10-µ-H-7,8-nidoC2B9H10][trans-Ir(CO)(PPh3)2(MeCN)](M = GeIV, SnIV) in which the Ph3M moiety interacts with the unique boron atom of the nido-C2B9via endo-σ-M–B bond as well as weak M–H–B bridge bond.

Synthesis, stereochemistry, mechanisms of formation, and X-ray crystal structures of enantiomerically pure π-allylpalladium compounds formed via palladium-promoted ring opening of bicyclic alkenes

The synthesis, stereochemistry, mechanisms of formation, and X-ray crystal structures of enantiomerically pure π-allylpalladium compounds (1)–(3) prepared by palladium hydride addition to (1R)-(+)-α-pinene, (1S)-(–)-α- or -β-pinene, and (1S)-(+)-2- or -3-carene respectively are presented.