A new class of 5-HT2B antagonists possesses favorable potency, selectivity, and rat pharmacokinetic properties

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 8, 2009, Pages 2206-2210

  Moss, Neil ^a   Choi, Younggi ^a   Cogan, Derek ^a   Flegg, Adam ^b   Kahrs, Andreas ^c   Loke, Pui ^b   Meyn, Orietta ^c   Nagaraja, Raj ^a   Napier, Spencer ^b   Parker, Ashley ^b   Thomas Peterson, J ^a   Ramsden, Philip ^a   Sarko, Christopher ^a   Skow, Donna ^a   Tomlinson, Josh ^b   Tye, Heather ^b   Whitaker, Mark ^b  

^a Cardiovascular Disease   (United States)

^b EVOTEC UK LTD   (United Kingdom)

^c EVOTEC AG   (Germany)

Author keywords

5 HT2B; Antagonist

Indexed keywords

AEQUORIN; HUMAN SERUM ALBUMIN; RS 127445; SB 215505; SEROTONIN 2 ANTAGONIST; SEROTONIN 2A RECEPTOR; SEROTONIN 2B ANTAGONIST; SEROTONIN 2B RECEPTOR; SEROTONIN 2C RECEPTOR; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG SELECTIVITY; DRUG STRUCTURE; HEART FAILURE; IC 50; LIPOPHILICITY; MALE; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; BINDING SITES; MALE; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP; RATS; RATS, SPRAGUE-DAWLEY; RATS, WISTAR; RECEPTOR, SEROTONIN, 5-HT2B; SEROTONIN ANTAGONISTS;

RATTUS;

EID: 63149086819     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.02.126     Document Type: Article

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19. We chose to use a serum shift assay to estimate the impact of protein binding because standard equilibrium dialysis experiments to determine protein binding are not high throughput and are not sensitive enough to distinguish between highly protein bound compounds. Rusnak D.W., Lai Z., Lansing T.J., Rhodes N., Gilmer T.M., and Copeland R.A. Bioorg. Med. Chem. Lett. 14 (2004) 2309 Using 4% HSA proved convenient as an estimate for the effect of serum components, since the use of serum in the assay stimulated calcium release presumably due to endogenous serotonin
20. The plasma protein binding for compound 1, RS-127445, and compound A were determined by equilibrium dialysis to be 99.9%, 99.9%, and 99%, respectively.
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22. 2A/C at concentrations up to ∼10 μM.
23. Most of the biaryl carboxylic acids are commercially available. So are the amine pieces in compounds 22, 25 and 27 which were coupled to biphenyl carboxylic acid by the options in Scheme 1. The azetidine fragment in compound 23 was prepared in the same manner as compound X.
24. HSA values for the training set range from -2.69 to +1.37 for low HSA to high HSA binding. The values for compounds 1, 16, 26 were calculated to be +1.01, +0.62, and +0.66 respectively.