Linda L. Chang

Substituted imidazoles as glucagon receptor antagonists.

A modestly active, nonselective triarylimidazole lead was optimized for binding affinity with the human glucagon receptor. This led to the identification of a 2- and/or 4-alkyl or alkyloxy substituent on the imidazole C4-aryl group as a structural determinant for significant enhancement in binding with the glucagon receptor (e.g., 41, IC(50)=0.053 microM) and selectivity (>1000x) over p38MAP kinase in this class of compounds.

The discovery of sulfonylated dipeptides as Potent VLA-4 antagonists

Directed screening of a carboxylic acid-containing combinatorial library led to the discovery of potent inhibitors of the integrin VLA-4. Subsequent optimization by solid-phase synthesis afforded a series of sulfonylated dipeptide inhibitors with structural components that when combined in a single hybrid molecule gave a sub-nanomolar inhibitor as a lead for medicinal chemistry. Preliminary metabolic studies led to the discovery of substituted biphenyl derivatives with low picomolar activities. SAR and pharmacokinetic characterization of this series are presented.

N-Tetrahydrofuroyl-(l)-phenylalanine derivatives as potent VLA-4 antagonists

Given the proposed involvement of VLA-4 in inflammatory processes, a program to identify orally active VLA-4 antagonists was initiated. Herein, we report the discovery of a N-tetrahydrofuroyl-(L)-phenylalanine derivative (17) and related analogues as potent VLA-4 antagonists with good oral bioavailability.

The discovery of small molecule carbamates as potent dual α4β1/α4β7 integrin antagonists

The alpha(4)beta(1) and alpha(4)beta(7) integrins are implicated in several inflammatory disease states. Systematic SAR studies of an alpha(4)beta(1)-specific arylsulfonyl-Pro-Tyr lead led to the identification of a new alpha(4)beta(7) binding site, best captured by O-carbamates of Tyr for this structural class. Several compounds showed a 200- to 400-fold improvement in alpha(4)beta(7) binding affinity while maintaining subnanomolar alpha(4)beta(1) activity, for example 2l, VCAM-Ig alpha(4)beta(1) IC(50)=0.13 nM, VCAM-Ig alpha(4)beta(7) IC(50)=1.92 nM.

Substituted tetrahydrofuroyl-1-phenylalanine derivatives as potent and specific VLA-4 antagonists.

A series of substituted tetrahydrofuroyl-1-phenylalanine derivatives was prepared and evaluated as VLA-4 antagonists. Substitution of the alpha carbon of the tetrahydrofuran with aryl groups increased the specificity for VLA-4 versus alpha(4)beta(7) while amide substitution increased the potency of the series without increasing the specificity. Substitution of the beta carbon of the tetrahydrofuran with keto or amino groups slightly improved the specificity for VLA-4 versus alpha(4)beta(7) but with a significant loss in binding affinity for VLA-4.

Substituted penta- and hexapeptides as potent inhibitors of herpes simplex virus type 2 ribonucleotide reductase

Abstract Structural modifications of the Tyr, Asn, and Leu residues of YVVNDL, a peptide which is equipotent to YAGAVVNDL in the inhibition of herpes simplex virus type 2 ribonucleotide reductase (HSV-2 RR), have produced peptides which are as much as 90- to 120-times as potent as YAGAVVNDL in vitro against HSV-2 RR. The chemistry and the structure activity relationships of these inhibitors are described. For the inhibition of herpes simplex virus type 2 ribonucleotide reductase (HSV-2 RR), structure-activity relationship studies on Y, N, and/or L of YVVNDL (equipotent to YAGAVVNDL on HSV-2 RR) using synthetic peptides are reported. The most potent of these, YVV-N(Nγ-Me2)-D-L(γ-Me), and (Bzl)2CHCO-VVND-L(γ-Me) had relative potencies of 110 and 120, respectively, relative to YAGAVVNDL.

Constraining the amide bond in N-Sulfonylated dipeptide VLA-4 antagonists

The integrin VLA-4 is implicated in several inflammatory disease states. In search of non-peptidic antagonists of VLA-4, rotational constraints were imposed on the amide bond of prototypical N-sulfonylated dipeptide VLA-4 antagonists. By judicious structural modification of the side chains, trisubstituted imidazoles with moderate binding potencies were obtained, for example, 19, VLA-4 IC(50)=237 nM.

Triazolinones as nonpeptide angiotensin II antagonists. 2. discovery of a potent and orally active triazolinone acylsulfonamide

Abstract A series of trisubstituted triazolinones with a [2′-(N-acylsulfamoy)biphenyl-4-yl]methyl side chain at N4 has been prepared. The inhibition of AII pressor responses by these potent AT1-selective AII antagonists indicated some of them to be superior in vivo to their tetrazole counterparts. At 1 mg/kg, 3d (L-159,913) was effective orally with > 4 h duration in dogs and had significant efficacy with > 10 h duration i.v. in chimpanzees.

Evaluation of endo- and exo-aryl-substitutions and central scaffold modifications on diphenyl substituted alkanes as 5-lipoxygenase activating protein inhibitors.

A search for a suitable replacement for the central norbornyl scaffold presented in the recently disclosed novel FLAP inhibitors is herein described, as well as the SAR study performed on the endo and exo-aryl groups.