title: Quality by design (QbD) of amide isosteres: 5,5-Disubstituted isoxazolines as potent CRTh2 antagonists with favorable pharmacokinetic and drug-like properties.
abstract: Isoxazoles are frequently used amide isosteres, as shown in the context of discovery of CRTh2 antagonists from amide 1 to isoxazole 2. However, persistent agonism and poor solubility in isoxazole series presented challenges to its further development. Based on the concept of quality by design (QbD), 5,5-disubstituted isoxazolines 3 were introduced. The chirality at 5 position of isoxazolines controlled the switch between two modes of actions, which led to a novel series of pure antagonists. This non-planar motif also conferred a change of shape of these molecules, which avoided flat structures and improved their physical properties.
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: dong.xiao@merck.com.
authors.forename: Dong
authors.initials: D
authors.lastname: Xiao
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Younong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Shao
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: McCormick
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Pawan
authors.initials: P
authors.lastname: Dhondi
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Mazzola
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Haiqun
authors.initials: H
authors.lastname: Tang
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Rao
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Phieng
authors.initials: P
authors.lastname: Siliphaivanh
authors.affiliation: In vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Hongchen
authors.initials: H
authors.lastname: Qiu
authors.affiliation: In vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Yang
authors.affiliation: In vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Rivelli
authors.affiliation: In vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Garlisi
authors.affiliation: Immunology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Eckel
authors.affiliation: Immunology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Gitali
authors.initials: G
authors.lastname: Mukhopadhyay
authors.affiliation: Immunology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Correll
authors.affiliation: Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Rindgen
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Aslanian
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Anandan
authors.initials: A
authors.lastname: Palani
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D004285:Dogs; D015195:Drug Design; D006207:Half-Life; D000882:Haplorhini; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D007555:Isoxazoles; D052999:Quinazolinones; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C036293:prostaglandin D2 receptor
keywords: Agonism/antagonism switch; Amide isostere; CRTh(2) antagonists; Drug-like properties; Isoxazolines; Quality by design (QbD)