Substituted piperazines as novel dipeptidyl peptidase IV inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 18, 2004, Pages 4763-4766

  Brockunier, Linda L ^a   He, Jiafang ^a   Colwell Jr , Lawrence F ^a   Habulihaz, Bahanu ^a   He, Huaibing ^a   Leiting, Barbara ^a   Lyons, Kathryn A ^a   Marsilio, Frank ^a   Patel, Reshma A ^a   Teffera, Yohannes ^a   Wu, Joseph K ^a   Thornberry, Nancy A ^a   Weber, Ann E ^a   Parmee, Emma R ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DIPEPTIDYL PEPTIDASE IV; DIPEPTIDYL PEPTIDASE IV INHIBITOR; FLUORINE; PEPTIDE HYDROLASE INHIBITOR; PHENYL GROUP; PIPERAZINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG HALF LIFE; DRUG POTENCY; DRUG SCREENING; DRUG SELECTIVITY; DRUG STRUCTURE; MOLECULAR WEIGHT; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION;

ADMINISTRATION, ORAL; ANIMALS; ANTIGENS, CD26; BIOLOGICAL AVAILABILITY; HALF-LIFE; MALE; MICROSOMES, LIVER; PIPERAZINES; PROTEASE INHIBITORS; RATS; RATS, SPRAGUE-DAWLEY; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 4544373020     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.06.065     Document Type: Article

References (11)

1. Xu, J.; Ok, H. O.; Gonzalez, E. J.; Colwell, L. F., Jr.; Habulihaz, B.; He, H.; Leiting, B.; Lyons, K. A.; Marsilio, F.; Patel, R. A.; Wu, J. K.; Thornberry, N. A.; Weber, A. E.; Parmee, E. R. Bioorg. Med. Chem. Lett. 2004, 14, preceding paper. doi:10.1016/j.bmcl.2004.06.099
2. The α- and β-amino amines were prepared by reductive amination of piperazine intermediate 5 with the requisite aldehydes. The aldehydes were available by lithium aluminum hydride reduction of the corresponding Weinreb amides
3. This work was reported in part; Brockunier, L. L. 227th National Meeting of the ACS, Anaheim, CA, March 2004. Abstract 100
4. 1H NMR, mass spectrometry and HPLC analysis
5. Requisite enatiomerically pure piperazines 6 were prepared according to a literature procedure outlined for the synthesis of (R) and (S)-2- methylpiperazine J.S. Kiely, and S.R. Priebe Org. Prep. Proced. Int. 22 1990 761
6. T.T. Shawe, G.J. Koenig, and A.A. Ross Synth. Commun. 27 1997 1777 Chromatographic separation provided the individual diastereomers
7. 50 determinations for DP-IV and other proline peptidases were carried out as described in: B. Leiting, K.D. Pryor, J.K. Wu, F. Marsilio, R.A. Patel, C.S. Craik, J.A. Ellman, R.T. Cummings, and N.A. Thornberry Biochem. J. 371 2003 525
8. 50 values were within 1.6-fold of the reported average; compound 31 was within 2.8-fold of the average. All QPP values were within 1.3-fold of the reported average
9. For references on proline specific peptidases see: J.S. Rosenblum, and J.W. Kozarich Curr. Opin. Chem. Biol. 7 2003 1
10. D.F. Cunningham, and B. O'Connor Biochim. Biophys. Acta 1343 1997 160
11. Male Sprague-Dawley rats were dosed intravenously at 1 mg/kg and orally at 2 mg/kg. Plasma drug levels were determined by LC/MS/MS