-
David G McLaren,
Timothy He,
Sheng-Ping Wang,
Vivienne Mendoza,
Raymond Rosa,
Karen Gagen,
Gowri Bhat,
Kithsiri Herath,
Paul L Miller,
Sloan Stribling, [......],
Shirly Pinto,
James M Balkovec, Robert J Devita,
Donald J Marsh,
Jose M Castro-Perez,
Alison Strack,
Douglas G Johns,
Stephen F Previs,
Brian K Hubbard,
Thomas P Roddy
[show abstract]
[hide abstract]
ABSTRACT: The use of stable isotopically labeled substrates and analysis by mass spectrometry have provided substantial insight into rates of synthesis, disposition, and utilization of lipids in vivo. The information to be gained from such studies is of particular benefit to therapeutic research where the underlying causes of disease may be related to the production and utilization of lipids. When studying biology through the use of isotope tracers, care must be exercised in interpreting the data to ensure that any response observed can truly be interpreted as biological and not as an artifact of the experimental design or a dilutional effect on the isotope. We studied the effects of dosing route and tracer concentration on the mass isotopomer distribution profile as well as the action of selective inhibitors of microsomal tri-glyceride transfer protein (MTP) in mice and diacylglycerol acyltransferase 1 (DGAT1) in nonhuman primates, using a stable-isotopically labeled approach. Subjects were treated with inhibitor and subsequently given a dose of uniformly ¹³C-labeled oleic acid. Samples were analyzed using a rapid LC-MS technique, allowing the effects of the intervention on the assembly and disposition of triglycerides, cholesteryl esters, and phospholipids to be determined in a single 3 min run from just 10 μl of plasma.
The Journal of Lipid Research 03/2011; 52(6):1150-61. · 5.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Ezetimibe (Zetia®), a cholesterol-absorption inhibitor (CAI) approved by the FDA for the treatment of hypercholesterolemia, is believed to target the intestine protein Niemann-Pick C1-Like 1 (NPC1L1) or its pathway. A spiroimidazolidinone NPC1L1 inhibitor identified by virtual screening showed moderate binding activity but was not efficacious in an in vivo rodent model of cholesterol absorption. Synthesis of analogs established the structure-activity relationships for binding activity, and resulted in compounds with in vivo efficacy, including 24, which inhibited plasma cholesterol absorption by 67% in the mouse, thereby providing proof-of-concept that non-β-lactams can be effective CAIs.
Bioorganic & medicinal chemistry letters 10/2010; 20(23):6929-32. · 2.65 Impact Factor
-
Gregori J Morriello,
Gary Chicchi,
Tricia Johnson,
Sander G Mills,
Julie Demartino,
Marc Kurtz,
K L C Tsao,
Song Zheng,
Xinchun Tong,
Emma Carlson,
Karen Townson,
Alan Wheeldon,
Susan Boyce,
Neil Collinson,
Nadia Rupniak, Robert J Devita
[show abstract]
[hide abstract]
ABSTRACT: Previously, we had disclosed a novel class of hNK(1) antagonists based on the 5,5-fused pyrrolidine core. These compounds displayed subnanomolar hNK(1) affinity along with good efficacy in a gerbil foot-tapping (GFT) model, but unfortunately they had low to moderate functional antagonist (IP-1) activity. To elaborate on the SAR of this class of hNK(1) compounds and to improve functional activity, we have designed and synthesized a new class of hNK(1) antagonist with a third fused ring. Compared to the 5,5-fused pyrrolidine class, these 5,5,5-fused tricyclic hNK(1) antagonists maintain subnanomolar hNK(1) binding affinity with highly improved functional IP-1 activity (<10% SP remaining). A fused tricyclic methyl, hydroxyl geminally substituted pyrrolizinone (compound 20) had excellent functional IP (<2% SP remaining), hNK(1) binding affinity, off-target selectivity, pharmacokinetic profile and in vivo activity. Complete inhibition of agonist activity was observed at both 0 and 24h in the gerbil foot-tapping model with an ID(50) of 0.02 mpk at both 0 and 24h, respectively.
Bioorganic & medicinal chemistry letters 10/2010; 20(19):5925-32. · 2.65 Impact Factor
-
Jianming Bao,
Huagang Lu,
Gregori J Morriello,
Emma J Carlson,
Alan Wheeldon,
Gary G Chicchi,
Marc M Kurtz,
Kwei-Lan C Tsao,
Song Zheng,
Xinchun Tong,
Sander G Mills, Robert J DeVita
[show abstract]
[hide abstract]
ABSTRACT: A new class of potent NK(1) receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK(1) receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK(1) binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P(450) inhibition and hPXR induction profiles.
Bioorganic & medicinal chemistry letters 02/2010; 20(7):2354-8. · 2.65 Impact Factor
-
Gregori J Morriello,
Sander G Mills,
Tricia Johnson,
Mikhail Reibarkh,
Gary Chicchi,
Julie DeMartino,
Marc Kurtz,
P Davies,
K L C Tsao,
Song Zheng,
Xinchun Tong,
Emma Carlson,
Karen Townson,
F D Tattersall,
Alan Wheeldon,
Susan Boyce,
Neil Collinson,
Nadia Rupniak,
Stephen Moore, Robert J DeVita
[show abstract]
[hide abstract]
ABSTRACT: Previous work on human NK(1) (hNK(1)) antagonists in which the core of the structure is a 5,5-fused pyrrolizinone has been disclosed. The structural-activity-relationship studies on simple alpha- and beta-substituted compounds of this series provided several potent and bioavailable hNK(1) antagonists that displayed excellent brain penetration as observed by their good efficacy in the gerbil foot-tapping (GFT) model assay. Several of these compounds exhibited 100% inhibition of the foot-tapping response at 0.1 and 24h with ID(50)'s of less than 1 mpk. One particular alpha-substituted compound (2b) had an excellent pharmacokinetic profile across preclinical species with reasonable in vivo functional activity and minimal ancillary activity.
Bioorganic & medicinal chemistry letters 01/2010; 20(6):2007-12. · 2.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: During our effort to design a receptor binding assay to aid in the elucidation of the molecular mechanism of ezetimibe, we prepared a sulfur-35 containing radioligand which exhibits improved potency over the glucuronide conjugate of ezetimibe in both native enterocyte brush border membranes and membranes from cells expressing recombinant NPC1L1. Herein, we describe the different synthetic strategies which were used to obtain this compound as well as its effectiveness in the aforementioned assay.
Bioorganic & medicinal chemistry letters 08/2009; 19(17):5033-6. · 2.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A series of spiroimidazolidinone NPC1L1 inhibitors was discovered by virtual screening of the Merck corporate sample repository using 3D-similarity-based screening. Selection of 330 compounds for testing in an in vitro NPC1L1 binding assay yielded six hits in six distinct chemical series. Follow-up 2D similarity searching yielded several sub- to low-micromolar leads; among these was spiroimidazolidinone 10, with an IC(50) of 2.5 microM. Compound 10 provided a useful scaffold to initiate a medicinal chemistry campaign.
Bioorganic & medicinal chemistry letters 07/2009; 19(11):2965-8. · 2.65 Impact Factor
-
Jinlong Jiang,
Jaime L Bunda,
Geoge A Doss,
Gary G Chicchi,
Marc M Kurtz,
Kwei-Lan C Tsao,
Xinchun Tong,
Song Zheng,
Alana Upthagrove,
Koppara Samuel, [......],
Alan Wheeldon,
Emma J Carlson,
Richard Hargreaves,
Donald Burns,
Terence Hamill,
Christine Ryan,
Stephen M Krause,
WaiSi Eng, Robert J DeVita,
Sander G Mills
[show abstract]
[hide abstract]
ABSTRACT: 3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one (17) is a high affinity, brain-penetrant, hydroisoindoline-based neurokinin-1 (NK(1)) receptor antagonist with a long central duration of action in preclinical species and a minimal drug-drug interaction profile. Positron emission tomography (PET) studies in rhesus showed that this compound provides 90% NK(1) receptor blockade in rhesus brain at a plasma level of 67 nM, which is about 10-fold more potent than aprepitant, an NK(1) antagonist marketed for the prevention of chemotherapy-induced and postoperative nausea and vomiting (CINV and PONV). The synthesis of this enantiomerically pure compound containing five stereocenters includes a Diels-Alder condensation, one chiral separation of the cyclohexanol intermediate, an ether formation using a trichloroacetimidate intermediate, and bis-alkylation to form the cyclic amine.
Journal of Medicinal Chemistry 05/2009; 52(9):3039-46. · 4.80 Impact Factor
-
Gregori J Morriello, Robert J Devita,
Sander G Mills,
Jonathan R Young,
Peter Lin,
George Doss,
Gary G Chicchi,
Julie Demartino,
Marc M Kurtz,
Kwei-Lan C Tsao,
Emma Carlson,
Karen Townson,
Alan Wheeldon,
Susan Boyce,
Neil Collinson,
Nadia Rupniak,
Stephen Moore
[show abstract]
[hide abstract]
ABSTRACT: Previous work on human NK(1) antagonists in which the core of the structure is a substituted pyrrolidine has been disclosed. These compounds showed good binding affinity and functional IP activity, however, many did not exhibit the necessary brain penetration for good in vivo activity. The discovery and preparation of a novel 5,5-fused pyrrolidine core is presented in this paper. This scaffold maintains the excellent binding affinity and functional IP activity of the previously reported compounds, but also exhibits excellent brain penetration as observed in a gerbil foot-tapping assay. The determination of the core structural stereochemistry, which eventually led to the final synthesis of a single active diastereomer, is described.
Bioorganic & medicinal chemistry 04/2008; 16(5):2156-70. · 2.82 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The preparation and structure-activity-relationships of novel pyrrolidine-carboxamides and oxadiazoles are described. Compounds in this series were found to be potent hNK(1) antagonists in vitro and efficacious in vivo with minimal interactions with P(450) liver enzymes. Oxadiazole analog 22 was determined to have excellent hNK(1) binding affinity, functional activity, and a good PD response in vivo.
Bioorganic & Medicinal Chemistry Letters 11/2007; 17(19):5310-5. · 2.55 Impact Factor
-
Peter Lin,
Lehua Chang, Robert J Devita,
Jonathan R Young,
Ronsar Eid,
Xinchun Tong,
Song Zheng,
Richard G Ball,
Nancy N Tsou,
Gary G Chicchi,
Marc M Kurtz,
Kwei-Lan C Tsao,
Alan Wheeldon,
Emma J Carlson,
Waisi Eng,
H Donald Burns,
Richard J Hargreaves,
Sander G Mills
[show abstract]
[hide abstract]
ABSTRACT: SAR studies on amides, ureas, and vinylogous amides derived from pyrrolidine led to the discovery of several potent hNK(1) antagonists. One particular vinylogous amide (45b) had excellent potency, selectivity, pharmacokinetic profile, and functional activity in vivo. An in vivo rhesus macaque brain receptor occupancy PET study for compound 45b revealed an estimated Occ(90) approximately 300 ng/ml.
Bioorganic & Medicinal Chemistry Letters 10/2007; 17(18):5191-8. · 2.55 Impact Factor
-
Robert J DeVita
[show abstract]
[hide abstract]
ABSTRACT: Structure-activity relationships of a 4-aminoquinoline MCH-1R antagonist lead series were explored by synthesis of analogs with modifications at the 2-, 4- and 6-positions of the original HTS hit. Improvements to the original screening lead were made by addition of lipophilic groups at the 2-position and biphenyl, cyclohexyl phenyl and hydrocinnamyl carboxamides at the 6-position. Viable modifications of the 4-amino group were limited and did not allow further optimization of the physical-chemical properties of this class of compounds. Transposition of the 4-amino group to the 2-position of the quinoline core structure provided the 2-aminoquinoline lead class with similar MCH1R binding affinity. A series of 2-aminoquinoline compounds was prepared and evaluated in MCH-1R binding and functional antagonist assays. Small dialkyl, methylalkyl, methylcycloalkyl and cyclic amines along with 3-substituted pyrrolidines were tolerated at the quinoline 2-position. The in vivo efficacy of compound A was explored and compared to that of a related inactive compound B to determine their effects on food intake and body weight in rodents. The biological activities of this matched active -inactive pair provide in vivo proof of concept in rodents that antagonism of MCH1R by a 2-aminoquinoline MCH1R antagonist which led to a reduction of food intake in an acute feeding assay paradigm.
Current topics in medicinal chemistry 02/2007; 7(15):1433-9. · 4.47 Impact Factor
-
Jinlong Jiang,
Peter Lin,
Myle Hoang,
Lehua Chang,
Carina Tan,
Scott Feighner,
Oksana C Palyha,
Donna L Hreniuk,
Jie Pan,
Andreas W Sailer,
Nancy R Morin,
Douglas J MacNeil,
Andrew D Howard,
Lex H T Van der Ploeg,
Mark T Goulet, Robert J DeVita
[show abstract]
[hide abstract]
ABSTRACT: Structure-activity relationships of a 4-aminoquinoline MCH1R antagonist lead series were explored by synthesis of analogs with modifications at the 2-, 4-, and 6-positions of the original HTS hit. Improvements to the original screening lead included lipophilic groups at the 2-position and biphenyl, cyclohexyl phenyl, and hydrocinnamyl carboxamides at the 6-position. Modifications of the 4-amino group were not well tolerated.
Bioorganic & Medicinal Chemistry Letters 11/2006; 16(20):5275-9. · 2.55 Impact Factor
-
Jinlong Jiang,
Myle Hoang,
Jonathan R Young,
Danny Chaung,
Ronsar Eid,
Cherilyn Turner,
Peter Lin,
Xinchun Tong,
Junying Wang,
Carina Tan, [......],
Andreas W Sailer,
Douglas J MacNeil,
Andrew Howard,
Lauren Shearman,
Sloan Stribling,
Ramon Camacho,
Alison Strack,
Lex H T Van der Ploeg,
Mark T Goulet, Robert J DeVita
[show abstract]
[hide abstract]
ABSTRACT: A series of 2-aminoquinoline compounds was prepared and evaluated in MCH1R binding and functional antagonist assays. Small dialkyl, methylalkyl, methylcycloalkyl, and cyclic amines were tolerated at the quinoline 2-position. The in vivo efficacy of compound 12 was explored and compared to that of a related inactive analog to determine their effects on food intake and body weight in rodents.
Bioorganic & Medicinal Chemistry Letters 11/2006; 16(20):5270-4. · 2.55 Impact Factor
-
Robert J DeVita,
Mamta Parikh,
Jinlong Jiang,
Jason A Fair,
Jonathan R Young,
Thomas F Walsh,
Mark T Goulet,
Jane-L Lo,
Ning Ren,
Joel B Yudkovitz,
Jisong Cui,
Yi T Yang,
Kang Cheng,
Susan P Rohrer,
Matthew J Wyvratt
[show abstract]
[hide abstract]
ABSTRACT: A series of neutral, nonbasic quinolone GnRH antagonists were prepared via Mitsunobu alkylation of protected and unprotected 4-hydroxy quinolone intermediates. The synthetic route was improved by utilization of unique reactivity and convergency afforded by the use of mono and bis-trimethylsilylethyl protected quinolones. Potent neutral GnRH antagonists were identified, including ether and lactam derivatives, that show similar in vitro binding affinity and functional activity as compared to the earlier basic 4-aminoalkyl quinolone series of nonpeptide GnRH antagonists.
Bioorganic & Medicinal Chemistry Letters 12/2004; 14(22):5599-603. · 2.55 Impact Factor
-
Jinlong Jiang, Robert J DeVita,
Mark T Goulet,
Matthew J Wyvratt,
Jane-L Lo,
Ning Ren,
Joel B Yudkovitz,
Jisong Cui,
Yi T Yang,
Kang Cheng,
Susan P Rohrer
[show abstract]
[hide abstract]
ABSTRACT: Syntheses and structure-activity relationships of piperidine-substituted quinolones as nonpeptide gonadotropin releasing hormone antagonists are described. Some of substituents on the piperidine ring that were investigated included a fused phenyl group, a (6R)-trifluoromethyl group, (6S) and (6R)-methyl group. This study showed that GnRH binding potency was tolerated by a small group at the 6-position of the piperidine, and blocking the 6-position by a trifluoromethyl group reduced clearance rate and increased oral bioavailability.
Bioorganic & Medicinal Chemistry Letters 05/2004; 14(7):1795-8. · 2.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: [reaction: see text]. A diastereoselective approach to the synthesis of 4-trifluoromethylated 2-alkyl- and 2,3-dialkylazetidines, including BOC-protected 4-trifluoromethylazetidin-2-ylcarboxylic acid, was developed via Wittig reaction of 4-trifluomethylated beta-lactam followed by alkylation and hydrogenation.
Organic Letters 10/2003; 5(22):4101-3. · 5.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In support of a program to develop a new gonadotropin releasing hormone (GnRH) receptor antagonist, two 14C labelled candidate tracers, 14C-1 and 14C-2, were synthesized for utilization in metabolism studies. A slight modification of the Medicinal Chemistry route for the synthesis of the antagonists provided iodide 4. Palladium (0) catalyzed [14C]carbonylation of 4 proceeded in good chemical yield to afford acid 14C-3 which served as a common precursor to 14C-1 and 14C-2. Copyright © 2003 John Wiley & Sons, Ltd.
Journal of Labelled Compounds 08/2003; 46(10):993 - 1000.
-
01/1999;
-
Robert J. DeVita,
Richard Bochis,
Alison J. Frontier,
Andrew Kotliar,
Michael H. Fisher,
William R. Schoen,
Matthew J. Wyvratt,
Kang Cheng,
Wanda W.-S. Chan,
Bridget Butler,
Thomas M. Jacks,
Gerard J. Hickey,
Klaus D. Schleim,
Kwan Leung,
Zhesheng Chen,
S.-H. Lee Chiu,
William P. Feeney,
Paul K. Cunningham,
Roy G. Smith
[show abstract]
[hide abstract]
ABSTRACT: The identification of L-739,943 (8b), a potent, orally bioavailable benzolactam growth hormone secretagogue, is obtained from zwitterionic L-692,429 through modification of its amino acid side chain and replacement of the acidic 2‘-tetrazole with the neutral and potency enhancing 2‘-(N-methylaminocarbonylamino)methyl substituent. L-739,943 is orally active for the release of growth hormone in beagle dogs at doses as low as 0.5 mg/kg. Oral bioavailability in dogs of 8b is 24% at a dose of 2 mg/kg with a mean drug Cmax of 145 ± 46 ng/mL. L-739,943 represents a significant breakthrough in terms of both potency and oral bioavailability as compared to the prototype benzolactam L-692,429.
04/1998;
