title: Thiophene carboxamide inhibitors of JAK2 as potential treatments for myleoproliferative neoplasms.
abstract: A series of carboxamide-substituted thiophenes demonstrating inhibition of JAK2 is described. Development of this chemical series began with the bioisosteric replacement of a urea substituent by a pyridyl ring. Issues of chemical and metabolic stability were solved using the results of both in vitro and in vivo studies, ultimately delivering compounds such as 24 and 25 that performed well in an acute PK/PD model measuring p-STAT5 inhibition.
authors.affiliation: Department of Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: andrew_haidle@merck.com.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Haidle
authors.affiliation: Department of Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Zabierek
authors.affiliation: Department of Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Kaleen K
authors.initials: KK
authors.lastname: Childers
authors.affiliation: Department of In Vitro Sciences, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Rosenstein
authors.affiliation: Department of Pharmacology, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Anjili
authors.initials: A
authors.lastname: Mathur
authors.affiliation: Department of Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Altman
authors.affiliation: Department of In Vitro Sciences, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Chan
authors.affiliation: Department of Drug Metabolism, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Bachman
authors.affiliation: Department of Pharmacology, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Jan-Rung
authors.initials: JR
authors.lastname: Mo
authors.affiliation: Department of Basic Pharmaceutical Sciences, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Melaney
authors.initials: M
authors.lastname: Bouthillette
authors.affiliation: Department of Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rush
authors.affiliation: Department of Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Tempest
authors.affiliation: Department of Oncology, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: C Gary
authors.initials: CG
authors.lastname: Marshall
authors.affiliation: Department of Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Young
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008954:Models, Biological; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D013876:Thiophenes; D000620:Aminoimidazole Carboxamide; D053614:Janus Kinase 2
keywords: Bioisostere; Inhibitor; JAK2; Metabolite identification; Polycythemia vera; Protein kinase; Thiophene