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Discovery of MK-8318, a Potent and Selective CRTh2 Receptor Antagonist for the Treatment of Asthma.
Huang, Xianhai; Brubaker, Jason; Zhou, Wei; Biju, Purakkattle J; Xiao, Li; Shao, Ning; Huang, Ying; Dong, Li; Liu, Zhidan; Bitar, Rema; Buevich, Alexei; Jung, Joon; Peterson, Scott L; Butcher, John W; Close, Joshua; Martinez, Michelle; MacCoss, Rachel N; Zhang, Hongjun; Crawford, Scott; McCormick, Kevin D; Aslanian, Robert; Nargund, Ravi; Correll, Craig; Gervais, Francois; Qiu, Hongchen; Yang, Xiaoxin; Garlisi, Charles; Rindgen, Diane; Maloney, Kevin M; Siliphaivanh, Phieng; Palani, Anandan.
Afiliación
  • Huang X; Discovery Chemistry, In Vitro Pharmacology, Drug Metabolism and Pharmacokinetics, and Process Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Brubaker J; Discovery Chemistry and Immunology, Merck Research Laboratory, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • Zhou W; Discovery Chemistry, In Vitro Pharmacology, Drug Metabolism and Pharmacokinetics, and Process Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Biju PJ; Discovery Chemistry, In Vitro Pharmacology, Drug Metabolism and Pharmacokinetics, and Process Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Xiao L; Discovery Chemistry, In Vitro Pharmacology, Drug Metabolism and Pharmacokinetics, and Process Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Shao N; Discovery Chemistry, In Vitro Pharmacology, Drug Metabolism and Pharmacokinetics, and Process Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Huang Y; Discovery Chemistry, In Vitro Pharmacology, Drug Metabolism and Pharmacokinetics, and Process Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Dong L; Discovery Chemistry, In Vitro Pharmacology, Drug Metabolism and Pharmacokinetics, and Process Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Liu Z; Discovery Chemistry, In Vitro Pharmacology, Drug Metabolism and Pharmacokinetics, and Process Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Bitar R; Discovery Chemistry, In Vitro Pharmacology, Drug Metabolism and Pharmacokinetics, and Process Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Buevich A; Discovery Chemistry, In Vitro Pharmacology, Drug Metabolism and Pharmacokinetics, and Process Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Jung J; Discovery Chemistry and Immunology, Merck Research Laboratory, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • Peterson SL; Discovery Chemistry and Immunology, Merck Research Laboratory, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • Butcher JW; Discovery Chemistry and Immunology, Merck Research Laboratory, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • Close J; Discovery Chemistry and Immunology, Merck Research Laboratory, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • Martinez M; Discovery Chemistry and Immunology, Merck Research Laboratory, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • MacCoss RN; Discovery Chemistry and Immunology, Merck Research Laboratory, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • Zhang H; Discovery Chemistry and Immunology, Merck Research Laboratory, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • Crawford S; Discovery Chemistry and Immunology, Merck Research Laboratory, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • McCormick KD; Discovery Chemistry, In Vitro Pharmacology, Drug Metabolism and Pharmacokinetics, and Process Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Aslanian R; Discovery Chemistry, In Vitro Pharmacology, Drug Metabolism and Pharmacokinetics, and Process Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Nargund R; Discovery Chemistry, In Vitro Pharmacology, Drug Metabolism and Pharmacokinetics, and Process Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Correll C; Discovery Chemistry and Immunology, Merck Research Laboratory, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • Gervais F; Discovery Chemistry and Immunology, Merck Research Laboratory, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • Qiu H; Discovery Chemistry, In Vitro Pharmacology, Drug Metabolism and Pharmacokinetics, and Process Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Yang X; Discovery Chemistry, In Vitro Pharmacology, Drug Metabolism and Pharmacokinetics, and Process Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Garlisi C; Discovery Chemistry, In Vitro Pharmacology, Drug Metabolism and Pharmacokinetics, and Process Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Rindgen D; Discovery Chemistry, In Vitro Pharmacology, Drug Metabolism and Pharmacokinetics, and Process Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Maloney KM; Discovery Chemistry, In Vitro Pharmacology, Drug Metabolism and Pharmacokinetics, and Process Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • Siliphaivanh P; Discovery Chemistry and Immunology, Merck Research Laboratory, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • Palani A; Discovery Chemistry, In Vitro Pharmacology, Drug Metabolism and Pharmacokinetics, and Process Chemistry, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
ACS Med Chem Lett ; 9(7): 679-684, 2018 Jul 12.
Article en En | MEDLINE | ID: mdl-30034600
ABSTRACT
A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists. The agonism and antagonism switch was achieved through structure-based drug design (SBDD) using a CRTh2 receptor homologue model. The challenge of very low exposures in pharmacokinetic studies was overcome by exhaustive medicinal chemistry lead optimization through focused SAR studies on the tricyclic core. Further optimization resulted in the identification of the preclinical candidate 4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid (15c, MK-8318) with potent and selective CRTh2 antagonist activity and a favorable PK profile suitable for once daily oral dosing for potential treatment of asthma.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos