(3R,4S)-4-(2,4,5-Trifluorophenyl)-pyrrolidin-3-ylamine inhibitors of dipeptidyl peptidase IV: Synthesis, in vitro, in vivo, and X-ray crystallographic characterization

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 20, 2007, Pages 5638-5642

  Wright, Stephen W ^a   Ammirati, Mark J ^a   Andrews, Kim M ^a   Brodeur, Anne M ^a   Danley, Dennis E ^a   Doran, Shawn D ^a   Lillquist, Jay S ^a   Liu, Shenping ^a   McClure, Lester D ^a   McPherson, R Kirk ^a   Olson, Thanh V ^a   Orena, Stephen J ^a   Parker, Janice C ^a   Rocke, Benjamin N ^a   Soeller, Walter C ^a   Soglia, Carolyn B ^a   Treadway, Judith L ^a   VanVolkenburg, Maria A ^a   Zhao, Zhengrong ^a   Cox, Eric D ^a  

^a PFIZER INC   (United States)

Author keywords

Diabetes; DPPIV inhibitors; Structure based design

Indexed keywords

4 (2,4,5 TRIFLUOROPHENYL)PYRROLIDIN 3 YLAMINE DERIVATIVE; DIPEPTIDYL PEPTIDASE IV INHIBITOR; PYRROLIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DOG; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; HIGH THROUGHPUT SCREENING; HUMAN; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; RAT; X RAY CRYSTALLOGRAPHY;

ANIMALS; ANTIGENS, CD26; CRYSTALLOGRAPHY, X-RAY; DOGS; FLUORINE; HUMANS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PROTEASE INHIBITORS; PYRROLIDINES; RATS; STEREOISOMERISM;

EID: 34548552525     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.07.081     Document Type: Article

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19. Analogs incorporating amides, amines, sulfonamides, and urea substituents placed on the pyrrolidine ring nitrogen atom were also evaluated; in general these were less potent as DPP4 inhibitors.
20. The application disclosing MK-0431 published concurrently with our efforts to increase potency by appropriate substitution of this phenyl ring; for example, a 2,5-difluorophenyl substitution improved potency to 61 nM from 790 nM for 10a. We obtained internal co-crystal structures using compounds similar to 2 and our pyrrolidine inhibitors and found a similar aryl binding mode in these structures. See Edmondson, D. D.; Parmee, E.; Weber, A. E.; Xu, J. Patent WO 03/000180, 2003; Chem. Abstr. 2003, 138, 73536.
21. D = 61° (c = 1.5, EtOH) was based upon agreement with protein crystal structures as well as identity to a sample of (+)12 prepared by diastereoselective azomethine ylide cycloaddition to (S)-4-phenyl-3-[(E)-3-(2,4,5-trifluoro-phenyl)-acryloyl]-oxazolidin-2- one; see U.S. Patent 5,618,949, 1997; Chem. Abstr. 1997, 126, 330549.
22. -1 in sterile saline. Pharmacodynamic determinations were made by assay of DPP4 activity in plasma samples taken from the PK study; see reference 7 for plasma DPP4 activity assay. PK and PD data for (+)15b are presented in the Supporting information.
23. 50 > 30 μM against DPP3, DPP9, FAP, and POP.
24. Compound (+)15b was dosed in fasted, diabetic KK/H1J mice and the response of the mice in an OGTT was measured; see Ref. 9. See Supporting information for in vivo glucose lowering data for (+)15b.
25. human), where BW, body weight, Fu, fraction unbound, CL, i.v. clearance, and 0.75, allometric scaling factor.