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Heather J Finlay,
Ji Jiang,
Yolanda Caringal,
Alexander Kover,
Mary Lee Conder,
Dezhi Xing,
Paul Levesque,
Timothy Harper,
Mei Mann Hsueh,
Karnail Atwal,
Michael Blanar,
Ruth Wexler, John Lloyd
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ABSTRACT: Previously disclosed C6 amido and benzimidazole dihydropyrazolopyrimidines were potent and selective blockers of I current. Syntheses and SAR for C6 triazolo and imidazo dihydropyrazolopyrimidines series are described. Trifluoromethylcyclohexyl N(1) triazole, compound 51, was identified as a potent and selective K1.5 inhibitor with an acceptable PK and liability profile.
Bioorganic & medicinal chemistry letters 03/2013; 23(6):1743-7. · 2.65 Impact Factor
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Heather J Finlay, John Lloyd,
Wayne Vaccaro,
Alexander Kover,
Lin Yan,
Gauri Bhave,
Joseph Prol,
Tram Huynh,
Rao Bhandaru,
Yolanda Caringal,
John DiMarco,
Jinping Gan,
Tim Harper,
Christine Huang,
Mary Lee Conder,
Huabin Sun,
Paul Levesque,
Michael Blanar,
Karnail Atwal,
Ruth Wexler
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ABSTRACT: Previously disclosed dihydropyrazolopyrimidines are potent and selective blockers of I(Kur) current. A potential liability with this chemotype is the formation of a reactive metabolite which demonstrated covalent binding to protein in vitro. When substituted at the 2 or 3 position, this template yielded potent I(Kur) inhibitors, with selectivity over hERG which did not form reactive metabolites. Subsequent optimization for potency and PK properties lead to the discovery of ((S)-5-(methoxymethyl)-7-(1-methyl-1H-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methanone (13j), with an acceptable PK profile in preclinical species and potent efficacy in the preclinical rabbit atrial effective refractory period (AERP) model.
Journal of Medicinal Chemistry 03/2012; 55(7):3036-48. · 4.80 Impact Factor
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John Lloyd,
Heather J Finlay,
Wayne Vacarro,
Tram Hyunh,
Alexander Kover,
Rao Bhandaru,
Lin Yan,
Karnail Atwal,
Mary Lee Conder,
Tonya Jenkins-West,
Hong Shi,
Christine Huang,
Danshi Li,
Huabin Sun,
Paul Levesque
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ABSTRACT: Design and synthesis of pyrazolodihydropyrimidines as KV1.5 blockers led to the discovery of 7d as a potent and selective antagonist. This compound showed atrial selective prolongation of effective refractory period in rabbits and was selected for clinical development.
Bioorganic & medicinal chemistry letters 02/2010; 20(4):1436-9. · 2.65 Impact Factor
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John Lloyd,
Heather J Finlay,
Karnail Atwal,
Alexander Kover,
Joseph Prol,
Lin Yan,
Rao Bhandaru,
Wayne Vaccaro,
Tram Huynh,
Christine S Huang,
Marylee Conder,
Tonya Jenkins-West,
Huabin Sun,
Danshi Li,
Paul Levesque
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ABSTRACT: Dihydropyrazolopyrimidines with a C6 heterocycle substituent were found to have high potency for block of K(V)1.5. Investigation of the substitution in the benzimidazole ring and the substituent in the 5-position of the dihydropyrazolopyrimidine ring produced 31a with an IC50 for K(V)1.5 block of 0.030muM without significant block of other cardiac ion channels. This compound also showed good bioavailability in rats and robust pharmacodynamic effects in a rabbit model.
Bioorganic & medicinal chemistry letters 08/2009; 19(18):5469-73. · 2.65 Impact Factor
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ABSTRACT: A series of dihydropyrazolopyrimidine inhibitors of K(V)1.5 (I(Kur)) have been identified. The synthesis, structure-activity relationships and selectivity against several other ion channels are described.
Bioorganic & medicinal chemistry letters 01/2009; 18(24):6381-5. · 2.65 Impact Factor
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ABSTRACT: The design and synthesis of a series of highly functionalized pyrano-[2,3b]-pyridines is described. These compounds were assayed for their ability to block the I(Kur) channel encoded by the gene hKV1.5 in patch-clamped L-929 cells. Six of the compounds in this series showed sub-micromolar activity, the most potent being 4-(4-ethyl-benzenesulfonylamino)-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3b]-pyridine-6-carboxylic acid ethyl-phenyl-amide with an IC(50) of 378 nM.
Bioorganic & medicinal chemistry letters 05/2008; 18(8):2714-8. · 2.65 Impact Factor
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ABSTRACT: We describe the development of a computational model for the prediction of the inhibition of K(+) flow through the hERG ion channel. Using a collection of 1075 discovery compounds with hERG inhibition measured in our standard patch-clamp electrophysiology assay, molecular features important for drug-induced inhibition were identified using a combination of statistical inference algorithms and manual hypothesis generation and testing. While many of the features used in the model reflect those referenced in the literature, several aspects of the model provide new insight into the role of physicochemical properties, electrostatics, and novel pharmacophores in hERG inhibition. Coefficients for these 10 features were then determined by least median squares regression, resulting in a model with an R(2) approximately 0.66 and RMS error (RMSe) of 0.47 log units for an external test set. Significant additional validation performed using a large collection of subsequent discovery data has been very encouraging with an R(2)=0.54 and an RMSe of 0.63 log units. The performance of the model across several different chemotypes is demonstrated and discussed.
Bioorganic & Medicinal Chemistry 10/2007; 15(18):6182-92. · 2.92 Impact Factor
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John Lloyd,
Karnail S Atwal,
Heather J Finlay,
Michael Nyman,
Tram Huynh,
Rao Bhandaru,
Alexander Kover,
Joan Schmidt,
Wayne Vaccaro,
Mary Lee Conder,
Tonya Jenkins-West,
Paul Levesque
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ABSTRACT: K(V)1.5 blockers have the potential to be atrium-selective agents for treatment of atrial fibrillation. The benzopyrans provide a template for the synthesis of potent and selective K(V)1.5 blockers.
Bioorganic & Medicinal Chemistry Letters 07/2007; 17(12):3271-5. · 2.55 Impact Factor
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Karnail S Atwal,
Saleem Ahmad,
Charles Z Ding,
Philip D Stein, John Lloyd,
Lawrence G Hamann,
David W Green,
Francis N Ferrara,
Paulina Wang,
W Lynn Rogers,
Lidia M Doweyko,
Arthur V Miller,
Sharon N Bisaha,
Joan B Schmidt,
Ling Li,
Kenneth J Yost,
Hsi-Jung Lan,
Cort S Madsen
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ABSTRACT: A series of substituted guanidine derivatives were prepared and evaluated as potent and selective inhibitors of mitochondrial F(1)F(0) ATP hydrolase. The initial thiourethane derived lead molecules possessed intriguing in vitro pharmacological profiles, though contained moieties considered non-drug-like. Analogue synthesis efforts led to compounds with maintained potency and superior physical properties. Small molecules in this series which potently and selectivity inhibit ATP hydrolase and not ATP synthase may have utility as cardioprotective agents.
Bioorganic & Medicinal Chemistry Letters 03/2004; 14(4):1027-30. · 2.55 Impact Factor
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Saleem Ahmad,
Lidia Doweyko,
Aaila Ashfaq,
Francis N Ferrara,
Sharon N Bisaha,
Joan B Schmidt,
John DiMarco,
Mary Lee Conder,
Tonya Jenkins-West,
Diane E Normandin,
Anita D Russell,
Mark A Smith,
Paul C Levesque,
Nicholas J Lodge, John Lloyd,
Philip D Stein,
Karnail S Atwal
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ABSTRACT: Class III anti-arrhythmic drugs (e.g., dofetilide) prolong cardiac action potential duration (APD) by blocking the fast component of the delayed rectifier potassium current (I(Kr)). The block of I(Kr) can result in life threatening ventricular arrhythmias (i.e., torsades de pointes). Unlike I(Kr), the role of the slow component of the delayed rectifier potassium current (I(Ks)) becomes significant only at faster heart rate. Therefore selective blockers of I(Ks) could prolong APD with a reduced propensity to cause pro-arrhythmic side effects. This report describes structure-activity relationships (SARs) of a series of I(Ks) inhibitors derived from 6-alkoxytetralones with good in vitro activity (IC(50) > or =30 nM) and up to 40-fold I(Ks)/I(Kr) selectivity.
Bioorganic & Medicinal Chemistry Letters 01/2004; 14(1):99-102. · 2.55 Impact Factor
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John Lloyd,
Joan B. Schmidt,
George Rovnyak,
Saleem Ahmad,
Karnail S. Atwal,
Sharon N. Bisaha,
Lidia M. Doweyko,
Philip D. Stein,
Sarah C. Traeger,
Arvind Mathur,
Mary Lee Conder,
John DiMarco,
Timothy W. Harper,
Tonya Jenkins-West,
Paul C. Levesque,
Diane E. Normandin,
Anita D. Russell,
Randolph P. Serafino,
Mark A. Smith,
Nicholas J. Lodge
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ABSTRACT: Multiple delayed rectifier potassium currents, including IKs, are responsible for the repolarization and termination of the cardiac action potential, and blockers of these currents may be useful as antiarrhythmic agents. Modification of compound 5 produced 19(S) that is the most potent IKs blocker reported to date with >5000-fold selectivity over other cardiac ion channels. Further modification produced 24A with 23% oral bioavailability.
10/2001;
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Bioorganic & Medicinal Chemistry Letters. 18(24):6381-6385.
