Discovery of VU6024578/BI02982816: An mGlu1 Positive Allosteric Modulator with Efficacy in Preclinical Antipsychotic and Cognition Models
Herein, we report progress toward a metabotropic glutamate receptor subtype 1 (mGlu1) positive allosteric modulator (PAM) clinical candidate and the discovery of VU6024578/BI02982816. From a weak high-throughput screening hit (VU0538160, EC50 > 10 μM, 71% Glumax), optimization efforts improved fu...
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| Veröffentlicht in: | Journal of medicinal chemistry 2024-12, Vol.67 (24), p.22291-22312 |
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| creator | Reed, Carson W. Kalbfleisch, Jacob F. Turkett, Jeremy A. Trombley, Trevor A. Nastase, Anthony F. Spearing, Paul K. Haymer, Daniel H. Sarwar, Mohammad Moshin Quitalig, Marc Dickerson, Jonathan W. Blobaum, Annie L. Boutaud, Olivier Voehringer, Patrizia Schuelert, Niklas Cho, Hyekyung P. Niswender, Colleen M. Rook, Jerri M. Priepke, Henning Ursu, Daniel Conn, P. Jeffrey Melancon, Bruce J. Lindsley, Craig W. |
| description | Herein, we report progress toward a metabotropic glutamate receptor subtype 1 (mGlu1) positive allosteric modulator (PAM) clinical candidate and the discovery of VU6024578/BI02982816. From a weak high-throughput screening hit (VU0538160, EC50 > 10 μM, 71% Glumax), optimization efforts improved functional potency over 185-fold to deliver the selective (inactive on mGlu2–5,7,8) and CNS penetrant (rat Kp = 0.99, Kp,uu = 0.82; MDCK-MDR1 ER = 1.7, Papp = 73 × 10–6 cm/s) mGlu1 PAM (VU6024578/BI02982816, EC50 = 54 nM, 83% Glumax). An excellent rat pharmacokinetic profile allowed the evaluation of VU6024578/BI02982816 in both amphetamine-induced hyperlocomotion (minimum effective dose (MED) = 3 mg/kg, p.o.) and MK-801 induced disruptions of novel object recognition (MED = 10 mg/kg p.o.), thus providing efficacy in preclinical models of psychosis and cognition. However, unanticipated AEs in dog prevented further consideration as a candidate. Thus, VU6024578/BI02982816 can serve as a best-in-class in vivo rodent tool to study selective mGlu1 activation. |
| doi_str_mv | 10.1021/acs.jmedchem.4c02554 |
| format | Article |
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From a weak high-throughput screening hit (VU0538160, EC50 > 10 μM, 71% Glumax), optimization efforts improved functional potency over 185-fold to deliver the selective (inactive on mGlu2–5,7,8) and CNS penetrant (rat Kp = 0.99, Kp,uu = 0.82; MDCK-MDR1 ER = 1.7, Papp = 73 × 10–6 cm/s) mGlu1 PAM (VU6024578/BI02982816, EC50 = 54 nM, 83% Glumax). An excellent rat pharmacokinetic profile allowed the evaluation of VU6024578/BI02982816 in both amphetamine-induced hyperlocomotion (minimum effective dose (MED) = 3 mg/kg, p.o.) and MK-801 induced disruptions of novel object recognition (MED = 10 mg/kg p.o.), thus providing efficacy in preclinical models of psychosis and cognition. However, unanticipated AEs in dog prevented further consideration as a candidate. 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Jeffrey</creatorcontrib><creatorcontrib>Melancon, Bruce J.</creatorcontrib><creatorcontrib>Lindsley, Craig W.</creatorcontrib><title>Discovery of VU6024578/BI02982816: An mGlu1 Positive Allosteric Modulator with Efficacy in Preclinical Antipsychotic and Cognition Models</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Herein, we report progress toward a metabotropic glutamate receptor subtype 1 (mGlu1) positive allosteric modulator (PAM) clinical candidate and the discovery of VU6024578/BI02982816. From a weak high-throughput screening hit (VU0538160, EC50 > 10 μM, 71% Glumax), optimization efforts improved functional potency over 185-fold to deliver the selective (inactive on mGlu2–5,7,8) and CNS penetrant (rat Kp = 0.99, Kp,uu = 0.82; MDCK-MDR1 ER = 1.7, Papp = 73 × 10–6 cm/s) mGlu1 PAM (VU6024578/BI02982816, EC50 = 54 nM, 83% Glumax). An excellent rat pharmacokinetic profile allowed the evaluation of VU6024578/BI02982816 in both amphetamine-induced hyperlocomotion (minimum effective dose (MED) = 3 mg/kg, p.o.) and MK-801 induced disruptions of novel object recognition (MED = 10 mg/kg p.o.), thus providing efficacy in preclinical models of psychosis and cognition. However, unanticipated AEs in dog prevented further consideration as a candidate. Thus, VU6024578/BI02982816 can serve as a best-in-class in vivo rodent tool to study selective mGlu1 activation.</description><issn>0022-2623</issn><issn>1520-4804</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNpVkc9OGzEQxq2KClLKG_TgI5cN_reOwwWFQCkSqBxKr5bX9hJHXjvY3qA8Am9dB3LpaTQz3_yk-T4AfmA0xYjgC6XzdD1Yo1d2mDKNSNuyL2CCW4IaJhA7AhOECGkIJ_QEfMt5jRCimNBjcELnnLcMtxPwfuOyjlubdjD28O8zR4S1M3FxfY_IXBCB-SVcBDjc-RHDp5hdcVsLF97HXGxyGj5GM3pVYoJvrqzgbd87rfQOugCfktXehdr7yihuk3d6FUs9UsHAZXwJlRbDHmF9_g6-9spne3aop-D55-2f5a_m4ffd_XLx0CjCcWkM0YbaboYYq8-YnlKLrVLcMGYM7YzQWnStoFp1ljBcpZxjalrR4bmmytBTcPXJ3Yzd3j4bSlJebpIbVNrJqJz8fxPcSr7ErcSYC1ZdqYTzAyHF19HmIodqovVeBRvHLClmH_bOeJWiT2lNS67jmEJ9TWIk9xHKj-EhQnmIkP4D1uOSCw</recordid><startdate>20241226</startdate><enddate>20241226</enddate><creator>Reed, Carson W.</creator><creator>Kalbfleisch, Jacob F.</creator><creator>Turkett, Jeremy A.</creator><creator>Trombley, Trevor A.</creator><creator>Nastase, Anthony F.</creator><creator>Spearing, Paul K.</creator><creator>Haymer, Daniel H.</creator><creator>Sarwar, Mohammad Moshin</creator><creator>Quitalig, Marc</creator><creator>Dickerson, Jonathan W.</creator><creator>Blobaum, Annie L.</creator><creator>Boutaud, Olivier</creator><creator>Voehringer, Patrizia</creator><creator>Schuelert, Niklas</creator><creator>Cho, Hyekyung P.</creator><creator>Niswender, Colleen M.</creator><creator>Rook, Jerri M.</creator><creator>Priepke, Henning</creator><creator>Ursu, Daniel</creator><creator>Conn, P. 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Thus, VU6024578/BI02982816 can serve as a best-in-class in vivo rodent tool to study selective mGlu1 activation.</abstract><pub>American Chemical Society</pub><pmid>39665415</pmid><doi>10.1021/acs.jmedchem.4c02554</doi><tpages>22</tpages><orcidid>https://orcid.org/0000-0003-0168-1445</orcidid><oa>free_for_read</oa></addata></record> |
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| title | Discovery of VU6024578/BI02982816: An mGlu1 Positive Allosteric Modulator with Efficacy in Preclinical Antipsychotic and Cognition Models |
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