Discovery of the Potent, Selective, Orally Available CXCR7 Antagonist ACT-1004-1239.

The chemokine receptor CXCR7, also known as ACKR3, is a seven-transmembrane G-protein-coupled receptor (GPCR) involved in various pathologies such as neurological diseases, autoimmune diseases, and cancers. By binding and scavenging the chemokines CXCL11 and CXCL12, CXCR7 regulates their extracellular levels. From an original high-throughput screening campaign emerged hit 3 among others. The hit-to-lead optimization led to the discovery of a novel chemotype series exemplified by the trans racemic compound 11i. This series provided CXCR7 antagonists that block CXCL11- and CXCL12-induced ß-arrestin recruitment. Further structural modifications on the trisubstituted piperidine scaffold of 11i yielded compounds with high CXCR7 antagonistic activities and balanced ADMET properties. The effort described herein culminated in the discovery of ACT-1004-1239 (28f). Biological characterization of ACT-1004-1239 demonstrated that it is a potent, insurmountable antagonist. Oral administration of ACT-1004-1239 in mice up to 100 mg/kg led to a dose-dependent increase of plasma CXCL12 concentration.

Verification of the Major Metabolic Oxidation Path for the Naphthoyl Group in Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTh2) Antagonist 2-(2-(1-Naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic Acid (Setipiprant/ACT-129968).

Various racemic and enantioenriched (trans)-X,Y-dihydroxy-X,Y-dihydronaphthoyl analogues as well as X-hydroxy-naphthoyl analogues of CRTh2 antagonist 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (1, Setipiprant/ACT-129968) were synthesized in order to gain insight into regio- and enantioselectivity of the metabolic oxidation of 1 and to verify the structures of four metabolites that were proposed earlier in a clinical ADME study. Analytical data of the synthetic standards were compared with data from samples of biological origin. The two major metabolites M7 and M9 were unambiguously verified as 2-(2-((trans)-3,4-dihydroxy-3,4-dihydronaphthalene-1-carbonyl)- and 2-(2-((trans)-5,6-dihydroxy-5,6-dihydronaphthalene-1-carbonyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid, respectively, each composed of two enantiomers with 68% and 44% ee in favor of (+)-(3S,4S)-M7 and (+)-(5S,6S)-M9, respectively. Likewise, minor metabolites M3 and M13 were identified as 2-(8-fluoro-2-(5-hydroxy-1-naphthoyl)- and 2-(8-fluoro-2-(4-hydroxy-1-naphthoyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)acetic acid, respectively.

Identification of 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (setipiprant/ACT-129968), a potent, selective, and orally bioavailable chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonist.

Herein we describe the discovery of the novel CRTh2 antagonist 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid 28 (setipiprant/ACT-129968), a clinical development candidate for the treatment of asthma and seasonal allergic rhinitis. A lead optimization program was started based on the discovery of the recently disclosed CRTh2 antagonist 2-(2-benzoyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid 5. An already favorable and druglike profile could be assessed for lead compound 5. Therefore, the lead optimization program mainly focused on the improvement in potency and oral bioavailability. Data of newly synthesized analogs were collected from in vitro pharmacological, physicochemical, in vitro ADME, and in vivo pharmacokinetic studies in the rat and the dog. The data were then analyzed using a traffic light selection tool as a visualization device in order to evaluate and prioritize candidates displaying a balanced overall profile. This data-driven process and the excellent results of the PK study in the rat (F = 44%) and the dog (F = 55%) facilitated the identification of 28 as a potent (IC50 = 6 nM), selective, and orally available CRTh2 antagonist.

Evolution of novel tricyclic CRTh2 receptor antagonists from a (E)-2-cyano-3-(1H-indol-3-yl)acrylamide scaffold.

(E)-2-(3-(3-((3-Bromophenyl)amino)-2-cyano-3-oxoprop-1-en-1-yl)-1H-indol-1-yl)acetic acid (1) was discovered in a HTS campaign for CRTh2 receptor antagonists. An SAR around this hit could be established and representatives with interesting activity profiles were obtained. Ring closing tactics to convert this hit series into a novel 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole based CRTh2 receptor antagonist series is presented.

Novel 2-(2-(benzylthio)-1H-benzo[d]imidazol-1-yl)acetic acids: discovery and hit-to-lead evolution of a selective CRTh2 receptor antagonist chemotype.

Hit-to-lead evolution of 2-(2-((2-(4-chlorophenoxy)ethyl)thio)-1H-benzo[d]imidazol-1-yl)acetic acid (1), discovered in a high-throughput screening campaign as a novel chemotype of CRTh2 receptor antagonist, is presented. SAR development as well as in vitro and in vivo DMPK properties of selected representatives of substituted 2-(2-(benzylthio)-1H-benzo[d]imidazol-1-yl)acetic acids are discussed.