Synthesis and structure-activity relationships for a series of substituted pyrrolidine NK1/NK2 receptor antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 7, Issue 19, 1997, Pages 2531-2536

  Burkholder, Timothy P ^a   Kudlacz, Elizabeth M ^a   Maynard, George D ^a   Liu, Xiao Gao ^a   Le, Tieu Binh ^a   Webster, Mark E ^a   Horgan, Stephen W ^a   Wenstrup, David L ^a   Freund, David W ^a   Boyer, Fred ^a   Bratton, Larry ^a   Gross, Raymond S ^a   Knippenberg, Robert W ^a   Logan, Deborah E ^a   Jones, Bryan K ^a   Chen, Teng Man ^a   Geary, Julie L ^a   Correll, Melinda A ^a   Poole, J Chuck ^a   Mandagere, Arun K ^a   Thompson, Thomas N ^a   Hwang, Kin Kai ^a   more..

^a SANOFI   (France)

Author keywords

[No Author keywords available]

Indexed keywords

1 [2 (PYRROLIDIN 3 YL) ETHYL]PIPERIDINE DERIVATIVE; CAPSAICIN; MDL 105212; NEUROKININ 1 RECEPTOR ANTAGONIST; NEUROKININ 2 RECEPTOR ANTAGONIST; TACHYKININ RECEPTOR ANTAGONIST; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; DRUG RECEPTOR BINDING; DRUG SYNTHESIS; ENANTIOMER; GUINEA PIG; HUMAN; HUMAN CELL; NONHUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; ORAL DRUG ADMINISTRATION; REACTION ANALYSIS; RECEPTOR AFFINITY; RESPIRATORY FUNCTION; STRUCTURE ACTIVITY RELATION;

EID: 18244423945     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)10013-0     Document Type: Article

References (29)

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14. Capsaicin is a sensory neurotoxin which causes the endogenous release of sensory neuropeptides including substance P and neurokinin A. see Maggi, C.A. J. Auton. Pharmac. 1991, 11, 173 and Lou, X.-P. Acta Physiol. Scand. Suppl. 1993, 612, 1.
15. Capsaicin is a sensory neurotoxin which causes the endogenous release of sensory neuropeptides including substance P and neurokinin A. see Maggi, C.A. J. Auton. Pharmac. 1991, 11, 173 and Lou, X.-P. Acta Physiol. Scand. Suppl. 1993, 612, 1.
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22. 2 receptors in HSKR-1 cells. Each value is the mean of at least 3 determinations. Receptor binding affinity has been determined by the experimental methods previously described (Kudlacz, E. M., Logan, D. E., Shatzer, S. A., Farrell, A. M., Baugh, L. E. Eur. J. Pharm. 1993, 241, 17).
23. The oral bioavailability of MDL 105,212 in the guinea pig with 40% HPβCD as vehicle was found to be 46%.
24. Other analogs that permeate Caco-2 cells better and show improved efficacy after oral administration, compared to MDL 105,212, will be reported in due course.
25. a, from which the log D was determined.
26. The solubility of MDL 105,212 analogs were determined in a 50 μM phosphate buffer solution at pH 7.4. Saturated solutions were obtained by sonicating the compounds in buffer for five min and then filtering through a Millex HV13 filter (Millipore). The concentrations of the compounds in the filtrate were quantified by HPLC, utilizing peak areas in comparison to an external standard.
27. 2 and approximately 95% humidity. For transport experiments apical samplings were taken at 0, 15, 30, 45, 60, 90, 120, 180, and 240 min after addition of test compound. MDL 105,212 analogs were snap frozen on dry ice/methanol and analyzed by HPLC. Phenytoin and Mannitol were evaluated as positive and negative controls and they permeated 8.5 times and 0.2 times as much as MDL 105,212A, respectively.
28. Each test substrate was incubated at an initial concentration of approximately 10 μM with rat liver 10S fortified with NADPH. The liver 10S was a pooled preparation so that each analog was incubated with the same preparation to factor out any intersample variability. The incubation took place for 60 min. The rate of disappearance of the test substrates was calculated from the slope of its disappearance curve over the initial linear portion of that curve. Metabolic stability was assessed by comparing the rates of each individual analog; compounds with the lowest rates are predicted to have the greatest metabolic stability.
29. This value is the average of the % inhibition of the capsaicin induced respiratory effects, as measured by the number of significant respiratory events (coughs and gasps), maximum pressure, and final pressure, from studies with conscious guinea pigs in a whole body plethysmograph one hour after oral administration of 10 mg/kg of test compound in HPβCD (see ref 1c for further details using this model with MDL 105,212).