Synthesis and structure-activity relationships of biarylcarboxamide bis-aminopyrrolidine urea derived small-molecule antagonists of the melanin-concentrating hormone receptor-1 (MCH-R1)

Bioorganic and Medicinal Chemistry Letters

Volumn 15, Issue 14, 2005, Pages 3439-3445

  Rowbottom, Martin W ^a   Vickers, Troy D ^a   Dyck, Brian ^a   Tamiya, Junko ^a   Zhang, Mingzhu ^a   Zhao, Liren ^a   Grey, Jonathan ^a   Provencal, David ^a   Schwarz, David ^a   Heise, Christopher E ^a   Mistry, Monica ^a   Fisher, Andrew ^a   Dong, Teresa ^a   Hu, Tao ^a   Saunders, John ^a   Goodfellow, Val S ^a  

^a NEUROCRINE BIOSCIENCES INC   (United States)

Author keywords

MCH; MCH antagonists; Melanin concentrating hormone; Obesity

Indexed keywords

AMIDE; MELANIN CONCENTRATING HORMONE; PYRROLIDINE DERIVATIVE; UREA DERIVATIVE;

ARTICLE; BINDING AFFINITY; BINDING ASSAY; DRUG SYNTHESIS; IN VITRO STUDY; METABOLISM; STRUCTURE ACTIVITY RELATION;

AMIDES; ANIMALS; DRUG DESIGN; MOLECULAR CONFORMATION; MOLECULAR WEIGHT; PYRROLIDINES; RATS; RECEPTORS, SOMATOSTATIN; STRUCTURE-ACTIVITY RELATIONSHIP; UREA;

EID: 20644445432     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.05.015     Document Type: Article

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21. Calculated using ACD/Labs Log P database, version 6.0 (2002), Advanced Chemistry Development Inc., Toronto, Ontario, Canada (http://www.acdlabs.com)
22. The diastereomeric purity of compound 5 was >98%, as measured by HPLC. This was determined by direct comparison to an equal mixture of both possible diastereomeric products, N-Boc protected (R)- and (S)-3-[(N-)methylamino] pyrrolidine-1-carboxylic acid [(R)-1-benzylpyrrolidin-3-yl]methylamide, which was prepared as described (Scheme 1) using commercially available racemic 3-pyrrolidinol hydrochloride
23. 2O: C, 52.50; H, 5.87; N, 10.20; S, 5.84. Found: C, 52.39; H, 6.22; N, 10.26; S, 6.23
24. i values were highly reproducible with an average standard deviation of <45% for replicate determinations. All compounds described were assayed in at least three independent experiments
25. 2+ flux assay, using cells stably expressing the hMCH-R1 receptor
26. 2+ flux functional assay
27. Cross-reactivity assays were performed by CEREP (www.cerep.com). For example, compound 12 displayed >500-fold selectivity when assayed against more than 75 GPCR receptors
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30. Inhibition assays were carried out using microsomes isolated from transfected cells expressing only the relevant CYP450 isoform (2D6 or 3A4) and in the presence of a fluorescent substrate (AMMC for 2D6 and BFC for 3A4). Quinidine and ketoconazole were used as positive controls for the CYP2D6 and 3A4 assays, respectively