Publications by authors named "Calum Macleod"

9 Publications

  • Page 1 of 1

Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model.

Bioorg Med Chem Lett 2017 09 12;27(18):4370-4376. Epub 2017 Aug 12.

Department of Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compound 1. Further optimization led to generation of compound 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compound 30 demonstrated dose-dependent reduction of IL-17 production in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL-17 decrease was accompanied by a reduction of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients.
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http://dx.doi.org/10.1016/j.bmcl.2017.08.022DOI Listing
September 2017

Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1.

J Med Chem 2015 Jun 4;58(12):5053-74. Epub 2015 Jun 4.

∇Argenta, A Charles River Company, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom.

Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development. A campaign of analogue synthesis established SAR delineating ChK1 and AChE activities and allowing identification of new leads with improved profiles. In silico docking using a model of AChE permitted rationalization of the observed SAR. Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailable ChK1 inhibitors offering excellent in vitro potency with significantly reduced AChE activity. In combination with gemcitabine, these compounds demonstrate an in vivo pharmacodynamic effect and are efficacious in a mouse p53 mutant xenograft model.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00464DOI Listing
June 2015

A restricted role for TYK2 catalytic activity in human cytokine responses revealed by novel TYK2-selective inhibitors.

J Immunol 2013 Sep 26;191(5):2205-16. Epub 2013 Jul 26.

Department of Immunology, Genentech, Inc., South San Francisco, CA 94080, USA.

TYK2 is a JAK family protein tyrosine kinase activated in response to multiple cytokines, including type I IFNs, IL-6, IL-10, IL-12, and IL-23. Extensive studies of mice that lack TYK2 expression indicate that the IFN-α, IL-12, and IL-23 pathways, but not the IL-6 or IL-10 pathways, are compromised. In contrast, there have been few studies of the role of TYK2 in primary human cells. A genetic mutation at the tyk2 locus that results in a lack of TYK2 protein in a single human patient has been linked to defects in the IFN-α, IL-6, IL-10, IL-12, and IL-23 pathways, suggesting a broad role for TYK2 protein in human cytokine responses. In this article, we have used a panel of novel potent TYK2 small-molecule inhibitors with varying degrees of selectivity against other JAK kinases to address the requirement for TYK2 catalytic activity in cytokine pathways in primary human cells. Our results indicate that the biological processes that require TYK2 catalytic function in humans are restricted to the IL-12 and IL-23 pathways, and suggest that inhibition of TYK2 catalytic activity may be an efficacious approach for the treatment of select autoimmune diseases without broad immunosuppression.
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http://dx.doi.org/10.4049/jimmunol.1202859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748334PMC
September 2013

Unusual underlying cause of recurrent vulval abscess.

BMJ Case Rep 2010 30;2010. Epub 2010 Mar 30.

Crosshouse Hospital, Obstetrics and Gynaecology, Crosshouse, Kilmarnock KA2 0JP, UK.

An ex-intravenous drug user was admitted four times during a 2 year period from December 2006, with the same complaint of vulval abscess which required repeat incision and drainage procedures. In January 2009, a pelvic x-ray showed widening of the symphysis pubis, marginal irregularities, and severe erosive changes which were consistent with pubic osteomyelitis. She was treated with intravenous ciprofloxacin and clindamycin for 2 weeks and was discharged on oral antibiotics for 6 weeks. She recovered well and her condition has significantly improved with no recurrent infection so far. She is now being followed up every 4-6 weeks at the orthopaedics outpatient clinic.
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http://dx.doi.org/10.1136/bcr.08.2009.2142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3030302PMC
October 2012

Annulation of primary amines to piperazines and diazaspirocycles utilizing alpha-methyl benzyl resin.

J Comb Chem 2006 Jan-Feb;8(1):132-40

Department of Chemistry, Adolor Corporation, 700 Pennsylvania Drive, Exton, Pennsylvania 19341, USA.

The microwave-assisted solid-phase synthesis of piperazines, 3,9-diazaspiro[5.5]undecanes and 2,9-diazaspiro[5.5]undecanes is reported. The synthesis relies on the direct annulation of primary amines with resin-bound bismesylates. Critical to the success of this chemistry was the development of alpha-methyl benzyl carbamate resin linker. This resin permits the cleavage of the heterocycles under mildly acidic conditions, free of contaminating linker-derived N-alkylated byproducts.
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http://dx.doi.org/10.1021/cc050106wDOI Listing
February 2006

Solid/solution-phase annulation reagents: single-step synthesis of cyclic amine derivatives.

Angew Chem Int Ed Engl 2005 Sep;44(36):5830-3

Department of Chemistry, Adolor Corporation, 700 Pennsylvania Drive, Exton, PA 19341, USA.

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http://dx.doi.org/10.1002/anie.200501665DOI Listing
September 2005

Teaching junior doctors to recognise child abuse and neglect.

Med Educ 2003 Nov;37(11):1046

Department of Paediatrics, Antrim Hospital, Antrim BT41 2RL, Northern Ireland, UK.

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http://dx.doi.org/10.1046/j.1365-2923.2003.01662.xDOI Listing
November 2003

Synthesis of 2-substituted benzofurans and indoles using functionalized titanium benzylidene reagents on solid phase.

J Org Chem 2003 Jan;68(2):387-401

Department of Chemistry, University of Glasgow, UK.

Titanium(IV) benzylidenes bearing a masked oxygen or nitrogen nucleophile in the ortho position were generated from thioacetals, using low-valent titanocene complex, Cp2Ti[P(OEt)3]2. Methylene acetal, alkyl ether, silyl ether, fluoro, tertiary amino, and N-alkyl, N-benzyl, N-prenyl, and N-silyl tert-butyl carbamate groups were tolerated in the titanium alkylidene reagents (Schrock carbenes). Aryl-chlorine bonds were stable to the titanium benzylidene functionality, but there was poor chemoselectivity for the reduction of the thioacetal in the presence of an aryl chloride. The titanium benzylidenes converted Merrifield and Wang resin-bound esters into enol ethers. The oxygen nucleophile was masked as a TMS ether, and when the resin-bound enol ethers bearing this ortho substituent were treated with 1% TFA in dichloromethane, benzofurans were released from resin in high yields. The chameleon catch strategy ensured excellent purity. In a similar way, N-alkylated and N-silylated tert-butyl carbamates were used for the synthesis of N-alkyl and N-Boc indoles, respectively. These traceless solid-phase syntheses of heterocycles are believed to involve postcleavage modification rather than cyclative termination.
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http://dx.doi.org/10.1021/jo026384oDOI Listing
January 2003

Novel functionalized titanium(IV) benzylidenes for the traceless solid-phase synthesis of indoles.

Org Lett 2002 Jan;4(1):75-8

Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK.

[reaction: see text] Titanium(IV) benzylidenes bearing a masked nitrogen nucleophile in the ortho position converted Merrifield resin-bound esters into enol ethers. An unusual nitrogen protecting group, N-silylated tert-butyl carbamate, was employed. One percent TFA released N-Boc indoles in high yield and purity. N-Methyl indoles were also prepared. Cyclative termination was not required to release the chameleon catch. The first example of a carbonyl group within a titanium alkylidene reagent is reported.
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http://dx.doi.org/10.1021/ol016924oDOI Listing
January 2002