Investigation of SAR requirements of SR 142801 through an indexed combinatorial library in solution

European Journal of Medicinal Chemistry

Volumn 34, Issue 10, 1999, Pages 825-835

  Raveglia, Luca F ^a   Vitali, Mauro ^c   Artico, Marco ^a   Graziani, Davide ^a   Hay, Douglas W P ^b   Luttmann, Mark A ^b   Mena, Renzo ^a   Pifferi, Giorgio ^c   Giardina, Giuseppe A M ^a  

^a SmithKline Beecham SpA   (Italy)

^b GLAXOSMITHKLINE   (United Kingdom)

^c Istituto di Chimica e Biochimica GRonzoni   (Italy)

Author keywords

Combinatorial chemistry; Indexed libraries; Neurokinin 3 receptor antagonists; Structure activity relationships; Tachykinins

Indexed keywords

NEUROKININ 3 RECEPTOR ANTAGONIST; OSANETANT;

ANIMAL CELL; ARTICLE; DRUG ACTIVITY; DRUG EFFECT; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; NONHUMAN; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS;

EID: 0032740516     PISSN: 02235234     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0223-5234(99)00210-X     Document Type: Article

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17. Being SR 142801 a single enantiomer about 2-fold more potent than the corresponding racemate (in-house data), the real difference in binding affinity for the hNK-3 receptor between X7AY2 and (±) SR 142801 is about 15-fold.
18. In house data demonstrate that SR 142801 has high systemic plasma clearance (36.9 ± 10.6 mL/min/kg) and low oral bioavailability (11 ± 2%) in rats; in addition, it showed significant interactions with some isoenzymes of P450 family (specifically, P2D6 and P3A4).