The design of potent and selective inhibitors of DPP-4: optimization of ADME properties by amide replacements.

For a series of beta-homophenylalanine based inhibitors of dipeptidyl peptidase IV ADME properties were improved by the incorporation of amide replacements. These efforts led to a novel series of potent and selective inhibitors of DPP-4 that exhibit an attractive pharmacokinetic profile and show excellent efficacy in an animal model of diabetes.

From lead to preclinical candidate: optimization of beta-homophenylalanine based inhibitors of dipeptidyl peptidase IV.

A series of highly potent and selective inhibitors of DPP-4 was optimized for ADMET properties. The effort resulted in the discovery of inhibitor 1g, that exhibits excellent efficacy in an oral glucose tolerance test and an attractive pharmacokinetic profile.

Discovery of beta-homophenylalanine based pyrrolidin-2-ylmethyl amides and sulfonamides as highly potent and selective inhibitors of dipeptidyl peptidase IV.

Modifications of DPP-4 inhibitor 5, that was discovered by structure based design, are described and structure-activity relationships discussed. With analogue 7k one of the most potent non-covalent inhibitors of DPP-4 reported to date (IC(50)=0.38nM) was discovered. X-ray structure of inhibitor 7k bound to DPP-4 revealed a hydrogen bonding interaction with Q553. First successful efforts in balancing overall properties, as demonstrated by improved metabolic stability, highlight the potential of this series.

From dihydroxypyrimidine carboxylic acids to carboxamide HIV-1 integrase inhibitors: SAR around the amide moiety.

4,5-Dihyroxypyrimidine carboxamides, which evolved from a related series of HCV NS5b polymerase inhibitors, have been optimized to provide selective HIV integrase strand transfer inhibitors. Extensive SAR around the benzylamide moiety led to the identification of the p-fluorobenzylamide as optimal in the enzymatic assay.

4,5-dihydroxypyrimidine carboxamides and N-alkyl-5-hydroxypyrimidinone carboxamides are potent, selective HIV integrase inhibitors with good pharmacokinetic profiles in preclinical species.

The dihydroxypyrimidine carboxamide 4a was discovered as a potent and selective HIV integrase strand transfer inhibitor. The optimization of physicochemical properties, pharmacokinetic profiles, and potency led to the identification of 13 in the dihydroxypyrimidine series and 18 in the N-methylpyrimidinone series having low nanomolar activity in the cellular HIV spread assay in the presence of 50% normal human serum and very good pharmacokinetics in preclinical species.

2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as inhibitors of the hepatitis C virus NS5B polymerase: discovery, SAR, modeling, and mutagenesis.

Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed dihydroxypyrimidine carboxylates 2 as novel, reversible inhibitors of the HCV NS5B polymerase. This series was further developed into 5,6-dihydroxy-2-(2-thienyl)pyrimidine-4-carboxylic acids such as 34 (EC50 9.3 microM), which now show activity in the cell-based HCV replication assay. The structure-activity relationship of these inhibitors is discussed in the context of their physicochemical properties and of the polymerase crystal structure. We also report the results of mutagenesis experiments which support the proposed binding model, which involves pyrophosphate-like chelation of the active site Mg ions.

The reversed binding of beta-phenethylamine inhibitors of DPP-IV: X-ray structures and properties of novel fragment and elaborated inhibitors.

The co-crystal structure of beta-phenethylamine fragment inhibitor 5 bound to DPP-IV revealed that the phenyl ring occupied the proline pocket of the enzyme. This finding provided the basis for a general hypothesis of a reverse binding mode for beta-phenethylamine-based DPP-IV inhibitors. Novel inhibitor design concepts that obviate substrate-like structure-activity relationships (SAR) were thereby enabled, and novel, potent inhibitors were discovered.

The design and enzyme-bound crystal structure of indoline based peptidomimetic inhibitors of hepatitis C virus NS3 protease.

The design of a series of peptidomimetic inhibitors of the hepatitis C virus NS3 protease is described. These inhibitors feature an indoline-2-carboxamide as a novel heterocyclic replacement for the P3 amino acid residue and N-terminal capping group of tripeptide based inhibitors. The crystal structure of the ternary NS3/NS4A/inhibitor complex for the most active molecule in this series highlights its suitability as an N-terminal capping group of a dipeptide inhibitor of the NS3 protease.

HCV NS5b RNA-dependent RNA polymerase inhibitors: from alpha,gamma-diketoacids to 4,5-dihydroxypyrimidine- or 3-methyl-5-hydroxypyrimidinonecarboxylic acids. Design and synthesis.

A new class of the HCV NS5b RNA-dependent RNA polymerase inhibitors, the dihyroxypyrimidinecarboxylic acid derivative, was designed from a diketoacid and meconic acid derivative discovered by screening. Mechanism of action and essential moieties required for activity were identified. The corresponding N-methylpyrimidinone was also prepared; both classes are novel, reversible, and selective inhibitors of the HCV NS5b polymerase with improved druglike characteristics.

SAR and pharmacokinetic studies on phenethylamide inhibitors of the hepatitis C virus NS3/NS4A serine protease.

SAR on the phenethylamide 1 (Ki 1.2 microM) in the P2- and the P'-position led to potent inhibitors, one of which showed good exposure and low clearance when administered intramuscularly to rat.

Capped dipeptide phenethylamide inhibitors of the HCV NS3 protease.

The N-terminal aminoacid of phenethylamide tripeptide inhibitors of the hepatitis C virus NS3 protease can be replaced with an alpha-hydroxy acid to obtain more 'drug like' inhibitors with low micromolar activity. The preferred S-configuration of the capping residue can be explained by molecular modeling studies.

Discovery of alpha,gamma-diketo acids as potent selective and reversible inhibitors of hepatitis C virus NS5b RNA-dependent RNA polymerase.

alpha,gamma-Diketo acids (DKA) were discovered from screening as selective and reversible inhibitors of hepatitis C virus NS5b RNA-dependent RNA polymerase. The diketo acid moiety proved essential for activity, while substitution on the gamma position was necessary for selectivity and potency. Optimization led to the identification of a DKA inhibitor of NS5b polymerase with IC(50) = 45 nM, one of the most potent HCV NS5b polymerase inhibitors reported.

Novel, potent phenethylamide inhibitors of the hepatitis C virus (HCV) NS3 protease: probing the role of P2 aryloxyprolines with hybrid structures.

Synthesis of hybrid HCV NS3 protease/NS4A inhibitors having the 4,4-difluoroaminobutyric acid (difluoroAbu) phenethylamides as P1-P1' and quinolyloxyprolines as P2 fragments led to 7 (IC(50) 54 nM). Molecular modelling suggests that this potent tripeptide inhibitor utilizes interactions in the S1', S1, S2, S3 and S4 sites of the protease.

Phenethyl amides as novel noncovalent inhibitors of hepatitis C virus NS3/4A protease: discovery, initial SAR, and molecular modeling.

The discovery of novel, reversible and competitive tripeptide inhibitors of the Hepatitis C virus NS3/4A serine protease is described. These inhibitors are characterized by the presence of a C-terminal phenethyl amide group, which extends into the prime side of the enzyme. Initial SAR together with molecular modeling and data from site-directed mutagenesis suggest an interaction of the phenethyl amide group with Lys-136.

Capped dipeptide alpha-ketoacid inhibitors of the HCV NS3 protease.

The N-terminal aminoacid of alpha-ketotripeptide inhibitors of the hepatitis C virus NS3 protease can be replaced with an alpha-hydroxy acid, leading to capped dipeptide inhibitors such as 20 with an IC(50) value of 3.0 microM. The importance of the lipophilic side chain interactions at S3 of the protease and the requirement of the capping residue with R configuration have been explained by molecular modeling studies.

A designed P1 cysteine mimetic for covalent and non-covalent inhibitors of HCV NS3 protease.

The difluoromethyl group was designed by computational chemistry methods as a mimetic of the canonical P1 cysteine thiol for inhibitors of the hepatitis C virus NS3 protease. This modification led to the development of competitive, non-covalent inhibitor 4 (K(i) 30 nM) and reversible covalent inhibitors (6, K(i) 0.5 nM; and 8 K*(i) 10 pM).

Evolution, synthesis and SAR of tripeptide alpha-ketoacid inhibitors of the hepatitis C virus NS3/NS4A serine protease.

N-terminal truncation of the hexapeptide ketoacid 1 gave rise to potent tripeptide inhibitors of the hepatitis C virus NS3 protease/NS4A cofactor complex. Optimization of these tripeptides led to ketoacid 30 with an IC50 of 0.38 microM. The SAR of these tripeptides is discussed in the light of the recently published crystal structures of a ternary tripetide/NS3/NS4A complexes.