title: Discovery and evaluation of 1H-pyrrolo[2,3-b]pyridine based selective and reversible small molecule BTK inhibitors for the treatment of rheumatoid arthritis.
abstract: In a pursuit to identify reversible and selective BTK inhibitors, two series based on 7H-pyrrolo[2,3-d]pyrimidine and 1H-pyrrolo[2,3-b]pyridine as the hinge binding core, have been identified. Structure activity relationship (SAR) exploration led to identification of two advanced lead molecules, 11 and 13, which demonstrated desired BTK inhibitory potency in different cellular assays, excellent selectivity in a panel of 50 diverse kinases, favorable in vivo PK properties in mice and anti-arthritic effect in a mouse model of CIA.
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: mahesh.thakkar@advinus.com.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Thakkar
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: debnath.bhuniya@advinus.com.
authors.forename: Debnath
authors.initials: D
authors.lastname: Bhuniya
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: rahul.kaduskar@advinus.com.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kaduskar
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: tanaji.m@advinus.com.
authors.forename: Tanaji
authors.initials: T
authors.lastname: Mengawade
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: keshav.naik@advinus.com.
authors.forename: Keshav
authors.initials: K
authors.lastname: Naik
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: videsh.salunkhe@advinus.com.
authors.forename: Videsh
authors.initials: V
authors.lastname: Salunkhe
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: amit.bhalerao@advinus.com.
authors.forename: Amit
authors.initials: A
authors.lastname: Bhalerao
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: santosh.kurhade@advinus.com.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kurhade
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: jagadeesh.m@advinus.com.
authors.forename: Jagadeesh
authors.initials: J
authors.lastname: Mavinahalli
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: vaibhav.jain@advinus.com.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Jain
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: rajkanth.petla@advinus.com.
authors.forename: Rajkanth
authors.initials: R
authors.lastname: Petla
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: satheesh.a@advinus.com.
authors.forename: Satheesh
authors.initials: S
authors.lastname: Avaragolla
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: swagatam.ray@advinus.com.
authors.forename: Swagatam
authors.initials: S
authors.lastname: Ray
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: sreekanth.r@advinus.com.
authors.forename: Sreekanth
authors.initials: S
authors.lastname: Rouduri
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: avinash.dhanave@advinus.com.
authors.forename: Avinash
authors.initials: A
authors.lastname: Dhanave
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: siddhartha.de@advinus.com.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: De
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: vishal.pathade@advinus.com.
authors.forename: Vishal
authors.initials: V
authors.lastname: Pathade
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: ashwini.tambe@advinus.com.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Tambe
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: amol.raje@advinus.com.
authors.forename: Amol A
authors.initials: AA
authors.lastname: Raje
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: vamsi.m@advinus.com.
authors.forename: Vamsi
authors.initials: V
authors.lastname: Madgula
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: sachin.joshi@advinus.com.
authors.forename: Sachin
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: ahmed.nadeem@advinus.com.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Nadeem
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: madhu.bala@advinus.com.
authors.forename: Madhu
authors.initials: M
authors.lastname: Bala
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: dhananjay.umrani@advinus.com.
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Umrani
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: hariharan.narayanan@advinus.com.
authors.forename: Narayanan
authors.initials: N
authors.lastname: Hariharan
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: kulkarni.b@advinus.com.
authors.forename: Bheemashankar
authors.initials: B
authors.lastname: Kulkarni
authors.affiliation: Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: kasim.mookhtiar@advinus.com.
authors.forename: Kasim A
authors.initials: KA
authors.lastname: Mookhtiar
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D018501:Antirheumatic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
chemical_list: D018501:Antirheumatic Agents; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C486292:pyrrolo(2, 3-b)pyridine
keywords: 1H-Pyrrolo[2,3-b]pyridine; Autoimmune diseases; BTK; Human whole blood; Kinase selectivity; Reversible; Rheumatoid arthritis