Publications by authors named "Neelakandha Mani"

35 Publications

Substituted Azabicyclo[2.2.1]heptanes as Selective Orexin-1 Antagonists: Discovery of JNJ-54717793.

ACS Med Chem Lett 2020 Oct 27;11(10):2002-2009. Epub 2020 Apr 27.

Janssen Research & Development L.L.C., 3210 Merryfield Row, San Diego, California 92121, United States.

The orexin system consists of two neuropeptides (orexin-A and orexin-B) that exert their mode of action on two receptors (orexin-1 and orexin-2). While the role of the orexin-2 receptor is established as an important modulator of sleep wake states, the role of the orexin-1 receptor is believed to play a role in addiction, panic, or anxiety. In this manuscript, we describe the optimization of a nonselective substituted azabicyclo[2.2.1]heptane dual orexin receptor antagonist (DORA) into orally bioavailable, brain penetrating, selective orexin-1 receptor (OX1R) antagonists. This resulted in the discovery of our first candidate for clinical development, JNJ-54717793.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsmedchemlett.0c00085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549262PMC
October 2020

LC/MS/MS Profiling of Tissue Oxysterols and its Application in Dextran Sodium Sulphate Induced Mouse Colitis Models.

Curr Top Med Chem 2017 ;17(24):2781-2790

Janssen R&D, LLC., 3210 Merryfield Row, San Diego, CA 92121. United States.

We have developed a workflow to extract, separate, and semi-quantify bioactive oxysterols from mouse colon tissues and fecal matters using solid- and liquid-phase extractions, enzymatic and chemical modifications, and stable-isotope dilution LC/MS/MS. The method was applied to a dextran sodium sulphate (DSS)-induced mouse colitis model, which revealed that one particular dihydroxycholesterol (diOHC), 7α,25-diOHC, was significantly elevated in both colon tissue and fecal matters of mice with colitis compared to that in naïve mice. The extent of 7α,25-diOHC elevation was positively correlated with colitis severity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1568026617666170713165519DOI Listing
September 2017

Gram-Scale Synthesis of a β-Secretase 1 (BACE 1) Inhibitor.

ACS Omega 2017 Feb 3;2(2):397-408. Epub 2017 Feb 3.

Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, California 92121, United States.

Development of a scalable synthesis of an oxazine class of β-secretase inhibitor is described. Trifluoromethylated acyloin synthesis by the reaction of a mandelic acid with trifluoroacetic anhydride in the presence of pyridine (Dakin-West reaction) was used as an efficient strategy to install the key trifluoromethyl substituent on the oxazine ring. Diastereoselective addition of methyl magnesium bromide to a cyclic sulfamidate imine and trimethylsilyl trifluoromethanesulfonate catalyzed intramolecular amidine formation to yield oxazine-3-amine are some of the significant, novel synthetic methods developed in this synthesis. These critical transformations allowed a concise 11-step route to the target compound with excellent overall yields.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsomega.6b00362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044763PMC
February 2017

Fluoro analogs of bioactive oxy-sterols: Synthesis of an EBI2 agonist with enhanced metabolic stability.

Bioorg Med Chem Lett 2016 10 12;26(20):4888-4891. Epub 2016 Sep 12.

Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States. Electronic address:

Synthesis of several 7-hydroxy oxysterols and their potential roles as signaling molecules in the innate and adaptive immune responses is discussed. Discovery of a new, fluorinated, synthetic analog of the 7α,25-dihydroxycholesterol-the endogenous ligand of GPR 183 (EBI2), a G-protein coupled receptor highly expressed upon Epstein-Barr virus infection is described. Fluoro oxysterol 12 showed good metabolic stability while maintaining excellent EBI2 agonist activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2016.09.029DOI Listing
October 2016

Regioselective Electrophilic Fluorination of Rationally Designed Imidazole Derivatives.

J Org Chem 2016 Feb 21;81(3):1269-76. Epub 2016 Jan 21.

Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.

We report the regioselective and direct functionalization of rationally designed imidazole derivatives through electrophilic fluorination with N-fluorobenzenesulfonimide enabled via in situ deprotonation with lithium 2,2,6,6-tetramethylpiperidine. Aided by a controlled protecting group switch, we were able to effectively target both the reactive 5- as well as the difficult to target 4-position of these molecules, leading to a series of fluorinated polysubstituted imidazoles in gram scale.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.joc.5b02592DOI Listing
February 2016

Allyl-Assisted, Cu(I)-Catalyzed Azide-Alkyne Cycloaddition/Allylation Reaction: Assembly of the [1,2,3]Triazolo-4,5,6,7-tetrahydropyridine Core Structure.

J Org Chem 2015 Nov 20;80(21):11003-12. Epub 2015 Oct 20.

Janssen Research & Development LLC , 3210 Merryfield Row, San Diego, California 92121, United States.

We report a Cu(I)-catalyzed azide-alkyne-allyl halide three-component reaction for a one-pot synthesis of 1,4-disubstituted 5-allyl-1,2,3-triazoles. The allyl moiety provides not only the electrophile but also a coordinating ligand to Cu, which is essential for the reaction to occur under mild conditions. A concise synthesis of a potential drug candidate 1 is realized based on this key reaction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.joc.5b02174DOI Listing
November 2015

Novel Octahydropyrrolo[3,4-c]pyrroles Are Selective Orexin-2 Antagonists: SAR Leading to a Clinical Candidate.

J Med Chem 2015 Jul 8;58(14):5620-36. Epub 2015 Jul 8.

The preclinical characterization of novel octahydropyrrolo[3,4-c]pyrroles that are potent and selective orexin-2 antagonists is described. Optimization of physicochemical and DMPK properties led to the discovery of compounds with tissue distribution and duration of action suitable for evaluation in the treatment of primary insomnia. These selective orexin-2 antagonists are proven to promote sleep in rats, and this work ultimately led to the identification of a compound that progressed into human clinical trials for the treatment of primary insomnia. The synthesis, SAR, and optimization of the pharmacokinetic properties of this series of compounds as well as the identification of the clinical candidate, JNJ-42847922 (34), are described herein.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.5b00742DOI Listing
July 2015

Novel benzamide-based histamine h3 receptor antagonists: the identification of two candidates for clinical development.

ACS Med Chem Lett 2015 Apr 13;6(4):450-4. Epub 2015 Mar 13.

Janssen Pharmaceutical Company, a division of Johnson & Johnson Pharmaceutical Research & Development L.L.C. , 3210 Merryfield Row, San Diego, California 92121, United States.

The preclinical characterization of novel phenyl(piperazin-1-yl)methanones that are histamine H3 receptor antagonists is described. The compounds described are high affinity histamine H3 antagonists. Optimization of the physical properties of these histamine H3 antagonists led to the discovery of several promising lead compounds, and extensive preclinical profiling aided in the identification of compounds with optimal duration of action for wake promoting activity. This led to the discovery of two development candidates for Phase I and Phase II clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ml5005156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394347PMC
April 2015

A step-economical route to fused 1,2,3-triazoles via an intramolecular 1,3-dipolar cycloaddition between a nitrile and an in situ generated aryldiazomethane.

J Org Chem 2014 Sep 9;79(18):8889-94. Epub 2014 Sep 9.

Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.

An intramolecular 1,3-dipolar cycloaddition strategy for rapid entry into triazole-fused heterocyclic compounds without recourse to the traditional Cu(1)-catalyzed azide-alkyne cycloadditions is described. Central to the strategy is the in situ generation of substituted diazomethanes in a two-step sequence from the corresponding aldehydes, which then undergo smooth cycloaddition with a cyano group to generate the desired fused 1,2,3-triazoles in good overall yields. The entire sequence can be carried out in a one-pot operation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo5013288DOI Listing
September 2014

Oxysterols are agonist ligands of RORγt and drive Th17 cell differentiation.

Proc Natl Acad Sci U S A 2014 Aug 4;111(33):12163-8. Epub 2014 Aug 4.

Janssen Research and Development, Spring House, PA 19002.

The RAR-related orphan receptor gamma t (RORγt) is a nuclear receptor required for generating IL-17-producing CD4(+) Th17 T cells, which are essential in host defense and may play key pathogenic roles in autoimmune diseases. Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol and lipid metabolism. Here, we describe the identification of several naturally occurring oxysterols as RORγt agonists. The most potent and selective activator for RORγt is 7β, 27-dihydroxycholesterol (7β, 27-OHC). We show that these oxysterols reverse the inhibitory effect of an RORγt antagonist, ursolic acid, in RORγ- or RORγt-dependent cell-based reporter assays. These ligands bind directly to recombinant RORγ ligand binding domain (LBD), promote recruitment of a coactivator peptide, and reduce binding of a corepressor peptide to RORγ LBD. In primary cells, 7β, 27-OHC and 7α, 27-OHC enhance the differentiation of murine and human IL-17-producing Th17 cells in an RORγt-dependent manner. Importantly, we showed that Th17, but not Th1 cells, preferentially produce these two oxysterols. In vivo, administration of 7β, 27-OHC in mice enhanced IL-17 production. Mice deficient in CYP27A1, a key enzyme in generating these oxysterols, showed significant reduction of IL-17-producing cells, including CD4(+) and γδ(+) T cells, similar to the deficiency observed in RORγt knockout mice. Our results reveal a previously unknown mechanism for selected oxysterols as immune modulators and a direct role for CYP27A1 in generating these RORγt agonist ligands, which we propose as RORγt endogenous ligands, driving both innate and adaptive IL-17-dependent immune responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1322807111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143045PMC
August 2014

Identification of structural motifs critical for epstein-barr virus-induced molecule 2 function and homology modeling of the ligand docking site.

Mol Pharmacol 2012 Dec 28;82(6):1094-103. Epub 2012 Aug 28.

Janssen Pharmaceutical Research and Development, San Diego, California, USA.

Epstein-Barr virus-induced molecule 2 (EBI2) (also known as G-protein-coupled receptor 183) is a G-protein-coupled receptor (GPCR) that is best known for its role in B cell migration and localization. Our recent deorphanization effort led to the discovery of 7α,25-dihydroxycholesterol (7α,25-OHC) as the endogenous ligand for EBI2, which provides a tool for mechanistic studies of EBI2 function. Because EBI2 is the first GPCR known to bind and to be activated by an oxysterol, the goal of this study was to understand the molecular and structural bases for its ligand-dependent activation; this was achieved by identifying structural moieties in EBI2 or in 7α,25-OHC that might affect receptor-ligand interactions. By using a series of chemically related OHC analogs, we demonstrated that all three hydroxyl groups in 7α,25-OHC contributed to ligand-induced activation of the receptor. To determine the location and composition of the ligand binding domain in EBI2, we used a site-directed mutagenesis approach and generated mutant receptors with single amino acid substitutions at selected positions of interest. Biochemical and pharmacological profiling of these mutant receptors allowed for structure-function analyses and revealed critical motifs that likely interact with 7α,25-OHC. By using a hybrid β(2)-adrenergic receptor-C-X-C chemokine receptor type 4 structure as a template, we created a homology model for EBI2 and optimized the docking of 7α,25-OHC into the putative ligand binding site, so that the hydroxyl groups interact with residues Arg87, Asn114, and Glu183. This model of ligand docking yields important structural insight into the molecular mechanisms mediating EBI2 function and may facilitate future efforts to design novel therapeutic agents that target EBI2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/mol.112.080275DOI Listing
December 2012

Direct, metal-free amination of heterocyclic amides/ureas with NH-heterocycles and N-substituted anilines in POCl3.

J Org Chem 2011 Oct 7;76(20):8262-9. Epub 2011 Sep 7.

Johnson & Johnson Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, California 92121, United States.

A POCl(3)-mediated, direct amination reaction of heterocyclic amides/ureas with NH-heterocycles or N-substituted anilines is described. Compared to the existing methods, this operationally simple protocol provides unique reactivity and functional group compatibility because of the metal-free, acidic reaction conditions. The yields are generally excellent.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo201425qDOI Listing
October 2011

Oxysterols direct B-cell migration through EBI2.

Nature 2011 Jul 27;475(7357):519-23. Epub 2011 Jul 27.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

EBI2 (also called GPR183) is an orphan G-protein-coupled receptor that is highly expressed in spleen and upregulated upon Epstein-Barr-virus infection. Recent studies indicated that this receptor controls follicular B-cell migration and T-cell-dependent antibody production. Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol metabolism. The biological effects of oxysterols have largely been credited to the activation of nuclear hormone receptors. Here we isolate oxysterols from porcine spleen extracts and show that they are endogenous ligands for EBI2. The most potent ligand and activator is 7α,25-dihydroxycholesterol (OHC), with a dissociation constant of 450 pM for EBI2. In vitro, 7α,25-OHC stimulated the migration of EBI2-expressing mouse B and T cells with half-maximum effective concentration values around 500 pM, but had no effect on EBI2-deficient cells. In vivo, EBI2-deficient B cells or normal B cells desensitized by 7α,25-OHC pre-treatment showed reduced homing to follicular areas of the spleen. Blocking the synthesis of 7α,25-OHC in vivo with clotrimazole, a CYP7B1 inhibitor, reduced the content of 7α,25-OHC in the mouse spleen and promoted the migration of adoptively transferred pre-activated B cells to the T/B boundary (the boundary between the T-zone and B-zone in the spleen follicle), mimicking the phenotype of pre-activated B cells from EBI2-deficient mice. Our results show an unexpected causal link between EBI2, an orphan G-protein-coupled receptor controlling B-cell migration, and the known immunological effects of certain oxysterols, thus uncovering a previously unknown role for this class of molecules.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature10226DOI Listing
July 2011

Protecting-group-free synthesis of a dual CCK1/CCK2 receptor antagonist.

Org Biomol Chem 2011 Apr 2;9(8):2654-60. Epub 2011 Mar 2.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, USA.

In our pursuit of an efficient, protecting-group-free synthesis of the dual CCK1/CCK2 receptor antagonist 1, we have developed chemoselective conditions for sulfonamide formation reaction in pure water and a PhNMe(2) mediated carboxamide formation, both in the presence of a carboxylic acid. Practical synthesis of an unnatural, chiral β-aryl-α-amino acid is also described.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c0ob01004aDOI Listing
April 2011

Practical and scalable synthesis of a selective CCK1 receptor antagonist.

J Org Chem 2010 Nov 27;75(22):7950-3. Epub 2010 Oct 27.

Johnson & Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, California 92121, United States.

We describe a practical and scalable route to compound (Z)-1, a selective CCK1 receptor antagonist. Notable features of this concise route are (1) a regioselective construction of the pyrazole core through the reaction of an aryl hydrazine and an elaborated acetylenic ketone, (2) a Tf2O/pyridine mediated Z-selective dehydration of an α-hydroxyester, and (3) a stereoselective hydrolysis. The sequence is high-yielding and amenable for large-scale synthesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo1017684DOI Listing
November 2010

Synthesis of a histamine H(3) receptor antagonist-manipulation of hydroxyproline stereochemistry, desymmetrization of homopiperazine, and nonextractive sodium triacetoxyborohydride reaction workup.

J Org Chem 2010 Jul;75(13):4463-71

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

We have recently completed the synthesis of 1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, a hydroxyproline-based H(3) receptor antagonist, on 100 g scale. The synthesis proceeds through four steps and route selection was driven by a desire to minimize the cost-of-goods. Naturally occurring trans-4-hydroxy-L-proline was chosen as the precursor to the target's core, which necessitated an inversion at both stereogenic centers. The inversions were accomplished through strategic employment of La Rosa's lactone and a late-stage Mitsunobu reaction. A first generation synthesis that employed N-Boc-homopiperazine was improved in a second generation approach wherein homopiperazine was directly desymmetrized. Finally, the water solubility of a key intermediate necessitated the development of a nonextractive workup for the sodium triacetoxyborohydride reduction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo100629zDOI Listing
July 2010

Practical synthesis of a Cathepsin S inhibitor: route identification, purification strategies, and serendipitous discovery of a crystalline salt form.

J Org Chem 2010 Mar;75(6):1940-7

Johnson & Johnson Pharmaceutical Research & Development LLC, 3210 Merryfield Row, San Diego, California 92121, USA.

A "redox economical" strategy resulted in a concise, modular synthesis of compound 1, a potent Cathepsin S inhibitor. Starting from three building blocks, crude drug substance was prepared in a two-step sequence in high yield. Efficient purification of the crude drug substance was accomplished via the formation of an unusual monoethyl oxalate salt.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo902650bDOI Listing
March 2010

Discovery and SAR of novel pyrazole-based thioethers as cathepsin S inhibitors: part 1.

Bioorg Med Chem Lett 2010 Apr 28;20(7):2370-4. Epub 2010 Jan 28.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of pyrazole-based thioethers were prepared and found to be potent cathepsin S inhibitors. A crystal structure of 13 suggests that the thioether moiety may bind to the S3 pocket of the enzyme. Additional optimization led to the discovery of aminoethylthioethers with improved enzymatic activity and submicromolar cellular potency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2010.01.108DOI Listing
April 2010

CuI-catalyzed amination of arylhalides with guanidines or amidines: a facile synthesis of 1-H-2-substituted benzimidazoles.

J Org Chem 2009 Aug;74(15):5742-5

Johnson & Johnson Pharmaceutical Research & Development, LLC 3210 Merryfield Row, San Diego, California 92121, USA.

CuI/L5 (N,N'-dimethylethylenediamine) proves to be an efficient catalyst system for the amination of arylhalides with guanidines. The same catalyst system is then successfully applied to the one-step synthesis of 1-H-2-amino-benzimidazoles through tandem aminations of 1,2-dihaloarenes in modest yields. This methodology is also applicable for the preparation of 1-H or 1-substutituted 2-aryl- or 2-alkyl-benzimidazoles.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo900912hDOI Listing
August 2009

An efficient intramolecular 1,3-dipolar cycloaddition involving 2-(1,2-dichlorovinyloxy)aryldiazomethanes: a one-pot synthesis of benzofuropyrazoles from salicylaldehydes.

J Org Chem 2009 Jan;74(2):891-4

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

A novel intramolecular 1,3-dipolar cycloaddition strategy for a rapid entry into benzofuropyrazoles is described. In a three-step sequence, (E)-2-(1,2-dichlorovinyloxy)aryldiazomethanes were generated in situ from the corresponding salicylaldehydes. Intramolecular cycloaddition followed by dehydrohalogenation garnered 3-chlorobenzofuropyrazoles in excellent yields. By careful choice of solvent, base, and reaction conditions, the entire sequence can be carried out in a one-pot procedure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo802193zDOI Listing
January 2009

Facile assembly of fused benzo[4,5]furo heterocycles.

J Org Chem 2008 Apr 11;73(7):2951-4. Epub 2008 Mar 11.

Johnson & Johnson Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

A concise synthesis of fused benzo[4,5]furo heterocycles 18 has been developed. Chemo/regioselective Suzuki coupling between 1,2-dihaloarene 17 and alpha-hydroxyphenylboronic acid or ester 20 gives biaryl phenol 19, which then undergoes copper(I) thiophene-2-carboxylate (CuTC)-mediated intramolecular cyclization to afford 18 in good overall yield. This method has broad substrate scope and allows facile assembly of a wide variety of benzo[4,5]furo heterocycles.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo8000595DOI Listing
April 2008

Base-mediated reaction of hydrazones and nitroolefins with a reversed regioselectivity: a novel synthesis of 1,3,4-trisubstituted pyrazoles.

Org Lett 2008 Mar 27;10(6):1307-10. Epub 2008 Feb 27.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

A regioselective synthesis of 1,3,4-tri- or 1,3,4,5-tetrasubstituted pyrazoles by the reaction of hydrazones with nitroolefins is described. Mediated with strong bases such as t-BuOK, the reaction exhibits a reversed, exclusive 1,3,4-regioselectivity. Subsequent quenching with strong acids such as TFA is essential to achieve good yields. A plausible stepwise cycloaddition reaction mechanism is proposed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ol800200jDOI Listing
March 2008

Regioselective synthesis of 1,3,5-tri- and 1,3,4,5-tetrasubstituted pyrazoles from N-arylhydrazones and nitroolefins.

J Org Chem 2008 Mar 16;73(6):2412-5. Epub 2008 Feb 16.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

Two general protocols are developed for the regioselective synthesis of 1,3,5-tri- and 1,3,4,5-tetrasubstituted pyrazoles by the reaction of electron-deficient N-arylhydrazones with nitroolefins. Studies on the stereochemistry of the key pyrazolidine intermediate suggest a stepwise cycloaddition mechanism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo7026195DOI Listing
March 2008

Design of concise, scalable route to a cholecystokinin 1 (CCK 1) receptor antagonist.

J Org Chem 2007 Oct 22;72(22):8243-50. Epub 2007 Sep 22.

Department of Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

Development of efficient, scalable routes for the synthesis of (S)-3-[5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-2-m-tolyl propionic acid, a selective cholecystokinin 1 (CCK 1) receptor antagonist, is described. A key feature of the scale-up route is a concise construction of the complete pyrazole framework in a single step by reacting an aryl hydrazine with an elaborated acetylenic ketone. This route was then further refined incorporating efficient enantioselective strategies to obtain the desired S-enantiomer in high optical purity. The first strategy involved an efficient, recyclable, kinetic resolution by enzyme-catalyzed hydrolysis of the racemic ester. In the second-generation route, the requisite stereochemistry at the chiral center was generated at an early stage in the synthesis involving a remarkable diastereoselective addition of inexpensive (S)-(-)-ethyl lactate to an alkylaryl ketene. Both methods furnished optically pure (>99% ee) final drug substance as its crystalline sodium salt.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo071166mDOI Listing
October 2007

Reactions between Weinreb amides and 2-magnesiated oxazoles: a simple and efficient preparation of 2-acyl oxazoles.

J Org Chem 2007 Jul 22;72(15):5828-31. Epub 2007 Jun 22.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

Treatment of oxazole or 5-aryl oxazoles with i-PrMgCl smoothly generates the corresponding 2-Grignard reagents, which react with Weinreb amides to provide exclusively 2-acyl oxazole products.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo070646aDOI Listing
July 2007

Novel pyrazole derivatives as potent inhibitors of type II topoisomerases. Part 1: synthesis and preliminary SAR analysis.

Bioorg Med Chem Lett 2007 May 6;17(10):2723-7. Epub 2007 Mar 6.

Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

In an attempt to search for a new class of antibacterial agents, we have discovered a series of pyrazole analogs that possess good antibacterial activity for Gram-positive and Gram-negative organisms via inhibition of type II bacterial topoisomerases. We have investigated the structure-activity relationships of this series, with an emphasis on the length and conformation of the linker. This work led to the identification of tetrahydroindazole analogs, such as compound 1, as the most potent class of compounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2007.03.003DOI Listing
May 2007

Synthesis of 4-arylpiperidines from 1-benzyl-4-piperidone: application of the Shapiro reaction and alkenylsilane cross-coupling.

Org Lett 2007 Apr 16;9(8):1505-8. Epub 2007 Mar 16.

Department of Drug Discovery, Johnson & Johnson Pharmaceutical R&D LLC, 3210 Merryfield Row, San Diego, California 92121, USA.

[reaction: see text] 1-Benzyl-3,4-unsaturated-4-piperidinyl benzyldimethylsilane has been prepared and observed to readily undergo palladium-catalyzed cross-coupling reactions with a variety of aryl iodides and aryl bromides to generate 3,4-unsaturated 4-arylpiperidines, often at ambient temperature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ol070241cDOI Listing
April 2007

Discovery of 6-N,N-bis(2,2,2-trifluoroethyl)amino- 4-trifluoromethylquinolin-2(1H)-one as a novel selective androgen receptor modulator.

J Med Chem 2006 Oct;49(21):6143-6

Discovery Research, Ligand Pharmaceuticals Inc., 10275 Science Center Drive, San Diego, California 92121, USA.

The androgen receptor is a member of the extended family of nuclear receptors and is widely distributed throughout the body. Androgen therapy is used to compensate for low levels of the natural hormones testosterone (T) and dihydrotestosterone and consists of administration of T, prodrugs thereof, or synthetic androgens. However, currently available androgens have many drawbacks. We identified 6-dialkylamino-4-trifluoromethylquinolin-2(1H)-ones as orally available tissue-selective androgen receptor modulators.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm060792tDOI Listing
October 2006

Reaction of N-monosubstituted hydrazones with nitroolefins: a novel regioselective pyrazole synthesis.

Org Lett 2006 Aug;8(16):3505-8

Department of Drug Discovery, Johnson & Johnson Pharmaceutical R&D LLC, 3210 Merryfield Row, San Diego, California 92121, USA.

A novel regioselective synthesis of substituted pyrazoles from N-monosubstituted hydrazones and nitroolefins is described. The reaction is performed in a one-pot manner and the yields range from moderate to excellent. A key nitropyrazolidine intermediate is characterized and a plausible mechanism is proposed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ol061226vDOI Listing
August 2006

Stereoselective synthesis of Z-alpha-aryl-alpha,beta-unsaturated esters.

J Org Chem 2006 Jun;71(13):5039-42

Department of Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

An efficient method for the stereoselective synthesis of (Z)-alpha-arylacrylates is described. Treatment of alpha-hydroxyesters with triflic anhydride and pyridine at 0 degrees C followed by warming to room temperature afforded the corresponding (Z)-alpha-aryl-alpha,beta-unsaturated esters in very good yields and excellent stereoselectivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo060586tDOI Listing
June 2006