Discovery of ((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran- 4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl) methanone, PF-4254196, a CCR2 antagonist with an improved cardiovascular profile

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 9, 2011, Pages 2626-2630

  Hughes, Robert O ^a   Rogier, D J ^a   Devraj, Rajesh ^a   Zheng, Changsheng ^b   Cao, Ganfeng ^b   Feng, Hao ^b   Xia, Michael ^b   Anand, Rajan ^b   Xing, Li ^a   Glenn, Joseph ^b   Zhang, Ke ^b   Covington, Maryanne ^b   Morton, Philip A ^a   Hutzler, J Matthew ^a   Davis II, John W ^a   Scherle, Peggy ^b   Baribaud, Fred ^b   Bahinski, Anthony ^a   Mo, Zun Li ^a   Newton, Robert ^b   Metcalf, Brian ^b   Xue, Chu Biao ^b   more..

^a PFIZER INC   (United States)

^b Experimental Station   (United States)

Author keywords

CCR2 antagonist; hERG; hERG homology model

Indexed keywords

[1 ISOPROPYL 3 (3 METHOXY TETRAHYDRO 2H PYRAN 4 YLAMINO)CYCLOPENTYL][4 [5 (TRIFLUOROMETHYL)PYRIDAZIN 3 YL]PIPERAZIN 1 YL]METHANONE; CHEMOKINE RECEPTOR CCR2 ANTAGONIST; PF 4254196; UNCLASSIFIED DRUG;

CARDIOVASCULAR EFFECT; CONFERENCE PAPER; DRUG CLEARANCE; DRUG IDENTIFICATION; DRUG STRUCTURE; HUMAN; HUMAN CELL; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ANTI-INFLAMMATORY AGENTS; BIOLOGICAL ASSAY; HUMANS; INHIBITORY CONCENTRATION 50; MICROSOMES; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PIPERAZINES; PROTEIN BINDING; PYRIDAZINES; RECEPTORS, CCR2; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 79955478571     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.01.034     Document Type: Conference Paper

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18. Log Ds were measured at pH 7.4.
19. All compounds described in this article are single enatiomers; generally, these compounds were purified from diastereomeric mixtures via chiral chromatography. The LHS of the molecules were installed by reductive alkylation resulting in the major isomers having the cis relationship between the amine and the beta substituent. For particularly interesting compounds, absolute stereochemical assignment was confirmed by X-ray crystallography.
20. Construction of a hERG homology model involved several computational treatments in sequence. Initially a crude model was built from the crystal structure of KcsA (PDB: 1K4C ) representing the closed sate of the ion channel. The model was then aligned onto the open form crystal structure of MthK (PDB: 1LNQ ), which was used as a guide to translate the initial model into an intermediate form between the closed and the opened states (BMCL, 2005, 15, 1737). Affording an outward rotation of S6 helices and re-optimization of the side chain conformations, the final model represents a partially open state and was used for docking the ligands. All homology modeling and energy optimization were conducted within Maestro molecular modeling suite (Schrodinger, Inc. www.schrodinger.com ). Compound 1 was docked into the hERG channel using FlexX (BioSolvIT GmbH, www.biolsolveit.de/flexx/ ) employing CONCORD generated three-dimensional conformation. No partial charges were precomputed and the FlexX parameters were set to default. More than a hundred docking poses were generated. Selection of the final pose was guided by docking scores as well as visual inspection of the modeled ligand-protein complex.
21. IV: 2mpk (n = 3)vehicle: 70% PEG400/20% 0.05 M citrate buffer/10% ethanol, pH 5; PO: 2 mpk (n = 3) vehicle: 0.5% methylcellulose/0.1% Tween 80 in 50 mM citric acid, pH 5; Cl = mL/min/kg.
22. For instance, wide ligand panel selectivity, genetic toxicity assays as well as multi-day toxicological studies in rat and cynomolgus.