Discovery and evaluation of 1H-pyrrolo[2,3-b]pyridine based selective and reversible small molecule BTK inhibitors for the treatment of rheumatoid arthritis

Mahesh Thakkar; Debnath Bhuniya; Rahul Kaduskar; Tanaji Mengawade; Keshav Naik; Videsh Salunkhe; Amit Bhalerao; Santosh Kurhade; Jagadeesh Mavinahalli; Vaibhav Jain; Rajkanth Petla; Satheesh Avaragolla; Swagatam Ray; Sreekanth Rouduri; Avinash Dhanave; Siddhartha De; Vishal Pathade; Ashwini Tambe; Amol A Raje; Vamsi Madgula; Sachin Joshi; Ahmed Nadeem; Madhu Bala; Dhananjay Umrani; Narayanan Hariharan; Bheemashankar Kulkarni; Kasim A Mookhtiar

doi:10.1016/j.bmcl.2017.02.026

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Discovery and evaluation of 1H-pyrrolo[2,3-b]pyridine based selective and reversible small molecule BTK inhibitors for the treatment of rheumatoid arthritis

Journal article

Peer reviewed

Discovery and evaluation of 1H-pyrrolo[2,3-b]pyridine based selective and reversible small molecule BTK inhibitors for the treatment of rheumatoid arthritis

Mahesh Thakkar, Debnath Bhuniya, Rahul Kaduskar, Tanaji Mengawade, Keshav Naik, Videsh Salunkhe, Amit Bhalerao, Santosh Kurhade, Jagadeesh Mavinahalli, Vaibhav Jain, …

Bioorganic & medicinal chemistry letters, Vol.27(8), pp.1867-1873

15/04/2017

DOI: https://doi.org/10.1016/j.bmcl.2017.02.026

PMID: 28279528

Abstract

Animals

Antirheumatic Agents - chemistry

Antirheumatic Agents - pharmacokinetics

Antirheumatic Agents - pharmacology

Antirheumatic Agents - therapeutic use

Arthritis, Rheumatoid - drug therapy

Arthritis, Rheumatoid - enzymology

Humans

Male

Mice, Inbred C57BL

Molecular Docking Simulation

Protein Kinase Inhibitors - chemistry

Protein Kinase Inhibitors - pharmacokinetics

Protein Kinase Inhibitors - pharmacology

Protein Kinase Inhibitors - therapeutic use

Protein-Tyrosine Kinases - antagonists & inhibitors

Protein-Tyrosine Kinases - metabolism

Pyridines - chemistry

Pyridines - pharmacokinetics

Pyridines - pharmacology

Pyridines - therapeutic use

Pyrroles - chemistry

Pyrroles - pharmacokinetics

Pyrroles - pharmacology

Pyrroles - therapeutic use

Structure-Activity Relationship

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.

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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
Creators - without role: Mahesh Thakkar - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: mahesh.thakkar@advinus.com
Debnath Bhuniya - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: debnath.bhuniya@advinus.com
Rahul Kaduskar - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: rahul.kaduskar@advinus.com
Tanaji Mengawade - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: tanaji.m@advinus.com
Keshav Naik - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: keshav.naik@advinus.com
Videsh Salunkhe - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: videsh.salunkhe@advinus.com
Amit Bhalerao - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: amit.bhalerao@advinus.com
Santosh Kurhade - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: santosh.kurhade@advinus.com
Jagadeesh Mavinahalli - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: jagadeesh.m@advinus.com
Vaibhav Jain - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: vaibhav.jain@advinus.com
Rajkanth Petla - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: rajkanth.petla@advinus.com
Satheesh Avaragolla - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: satheesh.a@advinus.com
Swagatam Ray - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: swagatam.ray@advinus.com
Sreekanth Rouduri - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: sreekanth.r@advinus.com
Avinash Dhanave - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: avinash.dhanave@advinus.com
Siddhartha De - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: siddhartha.de@advinus.com
Vishal Pathade - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: vishal.pathade@advinus.com
Ashwini Tambe - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: ashwini.tambe@advinus.com
Amol A Raje - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: amol.raje@advinus.com
Vamsi Madgula - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: vamsi.m@advinus.com
Sachin Joshi - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: sachin.joshi@advinus.com
Ahmed Nadeem - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: ahmed.nadeem@advinus.com
Madhu Bala - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: madhu.bala@advinus.com
Dhananjay Umrani - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: dhananjay.umrani@advinus.com
Narayanan Hariharan - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: hariharan.narayanan@advinus.com
Bheemashankar Kulkarni - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: kulkarni.b@advinus.com
Kasim A Mookhtiar - Drug Discovery Unit, Advinus Therapeutics Ltd, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411057, India. Electronic address: kasim.mookhtiar@advinus.com
Publication Details: Bioorganic & medicinal chemistry letters, Vol.27(8), pp.1867-1873
Identifiers: 9947843208331
Academic Unit: King Saud University
Language: English
Resource Type: Journal article