Discovery and Product Development

West Chester, PA, United States

Discovery and Product Development

West Chester, PA, United States

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News Article | May 18, 2017
Site: www.prnewswire.com

Nomination of this small-molecule candidate, discovered by Heptares using its structure-based design approach in partnership with Teva, has triggered a US$5 million payment from Teva to Heptares under the terms of their licensing and drug-discovery agreement signed in 2015. The nominated compound emerged from a rigorous Teva candidate selection process and has a highly differentiated profile from other investigational small-molecule CGRP antagonists, representing the first milestone in a partnership to generate novel candidates for the treatment of episodic and chronic migraine. "Teva is looking to build a sustainable leadership position in the treatment of migraine and headache," said Ralph Laufer, Teva R&D's Head of Discovery and Product Development unit. "This candidate has very interesting properties. While we still have a long way to go, we do see some characteristics in this molecule that could set it apart within the class, and look forward to continuing its development." "The discovery work conducted by Heptares and Teva has benefited from our combined expertise in the mechanism of CGRP in migraine. In particular, the unique structural insight we have gained concerning the interaction between CGRP and its receptor, a G protein-coupled receptor, has enabled the selection of a differentiated and highly selective small-molecule candidate," commented Malcolm Weir, CEO of Heptares and Chief R&D Officer of Sosei. Dr. Weir added, "Blocking the activity of CGRP is viewed increasingly as an attractive approach to treating migraine both acutely and preventatively, with several anti-CGRP antibodies in late-stage clinical trials. Small-molecule CGRP antagonists present a significant opportunity to address migraine even more effectively." Calcitonin gene-related peptide (CGRP) is released during migraine attacks and can trigger migraine in patients. CGRP is found in small to medium-sized neurons in the trigeminal ganglion and mediates its activity through G protein-coupled receptors located throughout the body. Elevated levels of CGRP are found in people with migraine during an attack and blocking CGRP activity is a validated mechanism of action for relieving pain, and also for preventing migraine. Approximately 36 million people in the United States and 8 million people in Japan suffer from migraine. Migraine is three times more common in women than in men and affects more than 10 percent of people worldwide. Migraine is defined as recurring attacks of moderate to severe headache pain, typically one-sided, throbbing and worse with activity. The International Headache Society defines chronic migraine as more than 15 headache days per month over a three-month period of which more than eight are migraine, in the absence of medication over use. Episodic migraine is the other migraine sub-type, which is defined as less than 15 headache days per month. During migraine, people can experience varying characteristics such as being very sensitive to light and sound or experiencing nausea and vomiting. There is no absolute cure for migraine since its pathophysiology has yet to be fully understood. Heptares is a clinical-stage company creating transformative medicines targeting G protein-coupled receptors (GPCRs), a superfamily of 375 receptors linked to a wide range of human diseases. Heptares' proprietary StaR® technology and structure-based drug design (SBDD) capabilities enable us to engineer and develop drugs for highly validated, yet historically undruggable or challenging GPCRs. Using this approach, we are building an exciting pipeline of new medicines (small molecules and biologics) with the potential to transform the treatment of Alzheimer's disease, schizophrenia, cancer immune-oncology, migraine, addiction, metabolic disease and other indications. We have partnerships for our novel candidates and technologies with leading pharmaceutical and biotechnology companies, including Allergan, AstraZeneca, Daiichi Sankyo, Kymab, MedImmune, MorphoSys, Pfizer and Teva. Heptares is a wholly owned subsidiary of Sosei Group Corporation. For more information, please visit http://www.heptares.com and http://www.sosei.com. HEPTARES is a registered trademark in the EU, Switzerland, US and Japan; StaR® is a registered trademark in the EU and Japan. Sosei is a biopharmaceutical company originating from Japan but with a global presence. Sosei's primary business model is based on identifying novel and/or differentiated product assets or technology platforms and, through supporting these in preclinical and clinical development and establishing commercial partnerships, advancing new medicines to patients worldwide. For more information about Sosei, please visit http://www.sosei.com.


News Article | May 18, 2017
Site: www.prnewswire.co.uk

Nomination of this small-molecule candidate, discovered by Heptares using its structure-based design approach in partnership with Teva, has triggered a US$5 million payment from Teva to Heptares under the terms of their licensing and drug-discovery agreement signed in 2015. The nominated compound emerged from a rigorous Teva candidate selection process and has a highly differentiated profile from other investigational small-molecule CGRP antagonists, representing the first milestone in a partnership to generate novel candidates for the treatment of episodic and chronic migraine. "Teva is looking to build a sustainable leadership position in the treatment of migraine and headache," said Ralph Laufer, Teva R&D's Head of Discovery and Product Development unit. "This candidate has very interesting properties. While we still have a long way to go, we do see some characteristics in this molecule that could set it apart within the class, and look forward to continuing its development." "The discovery work conducted by Heptares and Teva has benefited from our combined expertise in the mechanism of CGRP in migraine. In particular, the unique structural insight we have gained concerning the interaction between CGRP and its receptor, a G protein-coupled receptor, has enabled the selection of a differentiated and highly selective small-molecule candidate," commented Malcolm Weir, CEO of Heptares and Chief R&D Officer of Sosei. Dr. Weir added, "Blocking the activity of CGRP is viewed increasingly as an attractive approach to treating migraine both acutely and preventatively, with several anti-CGRP antibodies in late-stage clinical trials. Small-molecule CGRP antagonists present a significant opportunity to address migraine even more effectively." Calcitonin gene-related peptide (CGRP) is released during migraine attacks and can trigger migraine in patients. CGRP is found in small to medium-sized neurons in the trigeminal ganglion and mediates its activity through G protein-coupled receptors located throughout the body. Elevated levels of CGRP are found in people with migraine during an attack and blocking CGRP activity is a validated mechanism of action for relieving pain, and also for preventing migraine. Approximately 36 million people in the United States and 8 million people in Japan suffer from migraine. Migraine is three times more common in women than in men and affects more than 10 percent of people worldwide. Migraine is defined as recurring attacks of moderate to severe headache pain, typically one-sided, throbbing and worse with activity. The International Headache Society defines chronic migraine as more than 15 headache days per month over a three-month period of which more than eight are migraine, in the absence of medication over use. Episodic migraine is the other migraine sub-type, which is defined as less than 15 headache days per month. During migraine, people can experience varying characteristics such as being very sensitive to light and sound or experiencing nausea and vomiting. There is no absolute cure for migraine since its pathophysiology has yet to be fully understood. Heptares is a clinical-stage company creating transformative medicines targeting G protein-coupled receptors (GPCRs), a superfamily of 375 receptors linked to a wide range of human diseases. Heptares' proprietary StaR® technology and structure-based drug design (SBDD) capabilities enable us to engineer and develop drugs for highly validated, yet historically undruggable or challenging GPCRs. Using this approach, we are building an exciting pipeline of new medicines (small molecules and biologics) with the potential to transform the treatment of Alzheimer's disease, schizophrenia, cancer immune-oncology, migraine, addiction, metabolic disease and other indications. We have partnerships for our novel candidates and technologies with leading pharmaceutical and biotechnology companies, including Allergan, AstraZeneca, Daiichi Sankyo, Kymab, MedImmune, MorphoSys, Pfizer and Teva. Heptares is a wholly owned subsidiary of Sosei Group Corporation. For more information, please visit http://www.heptares.com and http://www.sosei.com. HEPTARES is a registered trademark in the EU, Switzerland, US and Japan; StaR® is a registered trademark in the EU and Japan. Sosei is a biopharmaceutical company originating from Japan but with a global presence. Sosei's primary business model is based on identifying novel and/or differentiated product assets or technology platforms and, through supporting these in preclinical and clinical development and establishing commercial partnerships, advancing new medicines to patients worldwide. For more information about Sosei, please visit http://www.sosei.com.


Roffey J.R.A.,University College London | Ott G.R.,Discovery and Product Development
Annual Reports in Medicinal Chemistry | Year: 2014

The atypical protein kinase C (PKC) isoforms (zeta and iota) have recently garnered attention as therapeutic targets for oncology, metabolic diseases as well as other indications. Though the novel and classical PKC isoforms have been interrogated as therapeutic intervention points and inhibitors of these isoforms (both selective and nonselective) have advanced to the clinic, no atypical inhibitor has been validated at this level. Recent biological studies have demonstrated the direct role for atypical PKC isoforms in specific cancers and the preclinical validity of atypical PKCs as therapeutic intervention points. This review will cover the structure/function of atypical PKCs versus novel and classical PKC isoforms, the implications in disease states, focusing on oncology, and a summary of both non-ATP competitive and ATP-competitive atypical PKC inhibitors. © 2014 Elsevier Inc.


Hudkins R.L.,Discovery and Product Development | Becknell N.C.,Discovery and Product Development | Lyons J.A.,Discovery and Product Development | Aimone L.D.,Discovery and Product Development | And 5 more authors.
European Journal of Medicinal Chemistry | Year: 2015

A novel series of 3,4-diaza-bicyclo[4.1.0]hept-4-en-2-ones were designed and synthesized as H3R analogs of irdabisant 6. Separation of the isomers, assignment of the stereochemistry by crystallography, and detailed profiling of diastereomers 25 and 26 led to the identification of (1R,6S)-5-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)propoxy]phenyl}-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one 25 as a potential second generation H3R candidate. Diastereomer 25 had high H3R binding affinity, excellent selectivity, displayed potent H3R functional antagonism and robust wake-promoting activity in vivo, and showed acceptable pharmacokinetic and pharmaceutical profiles for potential further development. © 2015 Elsevier Masson SAS.


Hudkins R.L.,Discovery and Product Development | Josef K.A.,Discovery and Product Development | Becknell N.C.,Discovery and Product Development | Aimone L.D.,Discovery and Product Development | And 4 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

A series of fused cyclopropyl-4,5-dihydropyridazin-3-one (3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one) phenoxypiperidine analogs was designed and synthesized, leading to the identification of (1R,6S)-5-[4-(1-cyclobutyl- piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a) as a second-generation pyridazin-3-one H3R antagonist. Compound R,S-4a was a potent H3R functional antagonist in vivo in the rat dipsogenia model, demonstrated potent wake activity in the rat EEG/EMG model, and enhanced short-term memory in the rat social recognition memory model at doses as low as 0.03-0.3 mg/kg po. © 2014 Elsevier Ltd. All rights reserved.


A series of fused cyclopropyl-4,5-dihydropyridazin-3-one (3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one) phenoxypiperidine analogs was designed and synthesized, leading to the identification of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a) as a second-generation pyridazin-3-one H3R antagonist. Compound R,S-4a was a potent H3R functional antagonist in vivo in the rat dipsogenia model, demonstrated potent wake activity in the rat EEG/EMG model, and enhanced short-term memory in the rat social recognition memory model at doses as low as 0.03-0.3 mg/kg po.


PubMed | Discovery and Product Development
Type: | Journal: European journal of medicinal chemistry | Year: 2015

A novel series of 3,4-diaza-bicyclo[4.1.0]hept-4-en-2-ones were designed and synthesized as H3R analogs of irdabisant 6. Separation of the isomers, assignment of the stereochemistry by crystallography, and detailed profiling of diastereomers 25 and 26 led to the identification of (1R,6S)-5-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)propoxy]phenyl}-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one 25 as a potential second generation H3R candidate. Diastereomer 25 had high H3R binding affinity, excellent selectivity, displayed potent H3R functional antagonism and robust wake-promoting activity invivo, and showed acceptable pharmacokinetic and pharmaceutical profiles for potential further development.

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