Discovery and Development of Highly Potent and Orally Bioavailable Nonpeptidic αβ Integrin Inhibitors.

A series of 3-aryl(()-3-fluoropyrrolidin-1-yl)butanoic acids were developed as potent orally bioavailable αβ integrin inhibitors. Starting from a zwitterionic peptidomimetic series optimized for inhaled administration, the balancing of potency and passive permeability to achieve suitable oral agents through modification and exploration of aryl substituents and p of the central cyclic amine is described. ()-4-(()-3-Fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-3-(3-(2-methoxyethoxy)phenyl)butanoic acid was found to have highly desirable oral pharmacokinetic profiles in rat, dog, and minipig, with low to moderate clearance (26%, 7%, and 18% liver blood flow, respectively), moderate volumes of distribution (3.

A Concise Enantioselective Synthesis of Fluorinated Pyrazolo-Piperidine GSK3901383A Enabled by an Organocatalytic Aza-Michael Addition.

A highly enantioselective organocatalytic aza-Michael addition of 4-nitro-pyrazole to ethyl ()-2,2-difluoro-5-oxopent-3-enoate has been developed. This reaction enabled a concise, four-step, stereoselective synthesis of highly functionalized 3,3-difluoro-4-pyrazolo-piperidine GSK3901383A, a key intermediate for the synthesis of a leucine-rich repeat kinase 2 inhibitor API. Computational analysis provided insight into the steric requirements of the catalytic system, enabling rational selection of a highly selective catalyst.

Discovery of ( S)-3-(3-(3,5-Dimethyl-1 H-pyrazol-1-yl)phenyl)-4-(( R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic Acid, a Nonpeptidic αβ Integrin Inhibitor for the Inhaled Treatment of Idiopathic Pulmonary Fibrosis.

A series of 3-aryl(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, via a rhodium catalyzed asymmetric 1,4-addition of arylboronic acids in the presence of ( R)-BINAP to a crotonate ester to provide the ( S) absolute configuration for the major product. A variety of aryl substituents including morpholine, pyrazole, triazole, imidazole, and cyclic ether were screened in cell adhesion assays for affinity against αβ, αβ, αβ, αβ, and αβ integrins. Numerous analogs with high affinity and selectivity for the αβ integrin were identified.

Synthesis and structure-activity relationships of indazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists.

A series of indazole arylsulfonamides were synthesized and examined as human CCR4 antagonists. Methoxy- or hydroxyl-containing groups were the more potent indazole C4 substituents. Only small groups were tolerated at C5, C6, or C7, with the C6 analogues being preferred.

Synthesis and pharmacological investigation of azaphthalazinone human histamine H(1) receptor antagonists.

5-Aza, 6-aza, 7-aza and 8-aza-phthalazinone, and 5,8-diazaphthalazinone templates were synthesised by stereoselective routes starting from the appropriate pyridine/pyrazine dicarboxylic acids by activation with CDI, reaction with 4-chlorophenyl acetate ester enolate to give a β-ketoester, which was hydrolysed, and decarboxylated. The resulting ketone was condensed with hydrazine to form the azaphthalazinone core. The azaphthalazinone cores were alkylated with N-Boc-D-prolinol at N-2 by Mitsunobu reaction, de-protected, and then alkylated at the pyrrolidine nitrogen to provide the target H(1) receptor antagonists.

Pyridyl-2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists: synthesis, pharmacokinetics, and in vivo potency.

A six-stage stereoselective synthesis of indanyl-7-(3'-pyridyl)-(3R,6R,7R)-2,5-diketopiperazines oxytocin antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3'-pyridyl ring and variation of the 3-isobutyl group gave potent compounds (pK(i) > 9.0) with good aqueous solubility.

Synthesis of arrays using low molecular weight MPEG-assisted Mitsunobu reaction.

Triphenylphosphine tagged with a short poly-(ethyleneglycol)-ω-monomethyl ether chain (light MPEG, 10−16 ethylenoxy units, (M)TPP-G2) and an MPEG-tagged version of diethyl azodicarboxylate ((M)DEAD) have been used to prepare a 20 member library of esters, ethers, and sulfonamides, with cLogP's in the range of 1.4−5.7 on a 0.

The discovery of phthalazinone-based human H1 and H3 single-ligand antagonists suitable for intranasal administration for the treatment of allergic rhinitis.

A series of potent phthalazinone-based human H(1) and H(3) bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis, were identified. Blockade of H(3) receptors is thought to improve efficacy on nasal congestion, a symptom of allergic rhinitis that is currently not treated by current antihistamines. Two analogues (56a and 56b) had slightly lower H(1) potency (pA(2) 9.

Low molecular weight MPEG-assisted organic synthesis.

A toolkit of low molecular weight MPEG-supported coupling agents ((M)IIDQ, (M)EDCI), reagents for the Mitsunobu reaction ((M)DEAD, (M)TPP), an alternative to diazomethane, and scavengers can be used in the solution-phase synthesis of amides, esters and ureas and are easily removed after use by solid-phase extraction (MSPE) using normal silica.

The discovery of GSK221149A: a potent and selective oxytocin antagonist.

Optimisation of a series of oxazole diketopiperazines has led to the discovery of a very potent and selective oxytocin antagonist GSK221149A. GSK221149A has been shown to inhibit oxytocin-induced uterine contractions in the anaesthetised rat.

2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists. 3. Synthesis, pharmacokinetics, and in vivo potency.

A short, efficient, and highly stereoselective synthesis of a series of (3R,6R,7R)-2,5-diketopiperazine oxytocin antagonists and their pharmacokinetics in rat and dog is described. Prediction of the estimated human oral absorption (EHOA) using measured lipophilicity (CHI log D) and calculated size (cMR) has allowed us to rank various 2,5-diketopiperazine templates and enabled us to focus effort on those templates with the greatest chance of high bioavailability in humans. This rapidly led to the 2',4'-difluorophenyl-dimethylamide 25 and the benzofuran 4 with high levels of potency (pK(i)) and good bioavailability in the rat and dog.

2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists. 2. Synthesis, chirality, and pharmacokinetics.

A short stereoselective synthesis of a series of chiral 7-aryl-2,5-diketopiperazines oxytocin antagonists is described. Varying the functionality and substitution pattern of substituents in the 7-aryl ring and varying the chirality of this exocyclic ring have produced potent oxytocin antagonists (pK(i) > 8.5).

Short and novel stereospecific synthesis of trisubstituted 2,5-diketopiperazines.

Novel syntheses of chiral trisubstituted 2,5-diketopiperazines using multicomponent Ugi reactions were developed.

2,5-Diketopiperazines as potent and selective oxytocin antagonists 1: Identification, stereochemistry and initial SAR.

This paper covers efforts to discover orally active potent and selective oxytocin antagonists. Screening pooled libraries identified a novel series of 2,5-diketopiperazine derivatives with antagonist activity at the human oxytocin receptor. We report the initial structure-activity relationship investigations and the determination of the stereochemistry of the most potent compounds.

Synthesis of a tetrasubstituted bicyclo [2.2.2] octane as a potential inhibitor of influenza virus sialidase.

A novel synthesis of the bicyclo [2.2.2] octane ring system has been achieved utilising a tandem Henry cyclisation as the key stage.

Sialidase inhibitors related to zanamivir: synthesis and biological evaluation of 4H-pyran 6-ether and ketone.

Synthesis of 5R-Acetamido-4S-amino-4H-pyran-6R-O-( -ethyl)propyl and 6R-(1-oxo-2-ethyl)butyl 2-carboxylic acids (4 and 5) and their evaluation as inhibitors of influenza virus sialidase is described. Both compounds showed good inhibitory activity with marked selectivity for influenza A sialidase.

Drug design against a shifting target: a structural basis for resistance to inhibitors in a variant of influenza virus neuraminidase.

Background: Inhibitors of the influenza virus neuraminidase have been shown to be effective antiviral agents in humans. Several studies have reported the selection of novel influenza strains when the virus is cultured with neuraminidase inhibitors in vitro. These resistant viruses have mutations either in the neuraminidase or in the viral haemagglutinin.

Dihydropyrancarboxamides related to zanamivir: a new series of inhibitors of influenza virus sialidases. 2. Crystallographic and molecular modeling study of complexes of 4-amino-4H-pyran-6-carboxamides and sialidase from influenza virus types A and B.

The first paper in this series (see previous article) described structure-activity studies of carboxamide analogues of zanamivir binding to influenza virus sialidase types A and B and showed that inhibitory activity of these compounds was much greater against influenza A enzyme. To understand the large differences in affinities, a number of protein-ligand complexes have been investigated using crystallography and molecular dynamics. The crystallographic studies show that the binding of ligands containing tertiary amide groups is accompanied by the formation of an intramolecular planar salt bridge between two amino acid residues in the active site of the enzyme.

Dihydropyrancarboxamides related to zanamivir: a new series of inhibitors of influenza virus sialidases. 1. Discovery, synthesis, biological activity, and structure-activity relationships of 4-guanidino- and 4-amino-4H-pyran-6-carboxamides.

4-Amino- and 4-guanidino-4H-pyran-6-carboxamides 4 and 5 related to zanamivir (GG167) are a new class of inhibitors of influenza virus sialidases. Structure--activity studies reveal that, in general, secondary amides are weak inhibitors of both influenza A and B viral sialidases. However, tertiary amides, which contain one or more small alkyl groups, show much greater inhibitory activity, particularly against the influenza A virus enzyme.