Progress Report: PHGDH ACT Domain — Lead Optimization for CNS-Penetrant AD Therapeutic (Cycle 14)

Executive Summary

This cycle, we continued to refine the MCDA scores and identify the best candidates for CNS-penetrant AD therapeutic development. Rankings unchanged from Cycle 13.

Research Progress

In this cycle, we further refined the MCDA scores and identified the best candidates for CNS-penetrant AD therapeutic development. We also explored new analogs and scaffolds to improve the overall ranking.

Key Findings

[Output] Cycle 14 Validation & Final MCDA Ranking

cycle14_mcda.csv

compound_name	smiles	logBB_predicted	cns_mpo_score	bbb_penetration	bbb_cns_penetration	note	synthesizability_score	rbd_mechanistic_evidence	rbd_mechanistic_evidence__src	bbb_cns_penetration__src	synthesizability_score__src	ip_translational_novelty	ip_translational_novelty__src	type	canonical_smiles	chembl_id	inchikey	molecular_weight	alogp
NCT-503	CC(C)CCn1c(CN2CCN(C(=O)C3CC3)CC2)nc2c1c(…	-0.98	3.64	3	4	Predicted values only — experimental con…	5	5	tool	tool	tool	4	tool	pharmacological agent	CC(C)CCn1c(CN2CCN(C(=O)C3CC3)CC2)nc2c1c(…	CHEMBL5723364	MQNBJYUQFQUJQZ-UHFFFAOYSA-N	416.53	0.53
BI-4924	Cl.O=C1Nc2ccc(Br)cc2C12NCCc1c2[nH]c2cccc…	-0.14	2.67	3	3	Predicted values only — experimental con…	4	5	tool	tool	tool	5	tool	pharmacological agent	Cl.O=C1Nc2ccc(Br)cc2C12NCCc1c2[nH]c2cccc…	CHEMBL585611	KAWDJXZLBBFNQQ-UHFFFAOYSA-N	368.23	3.27
CHEMBL496594	N#Cc1cnc2c(Cl)cc(NCc3cn(CCN4CCCCCC4)nn3)…				3		5	5	tool	tool	tool	4	tool	Small molecule	N#Cc1cnc2c(Cl)cc(NCc3cn(CCN4CCCCCC4)nn3)…	CHEMBL496594	ZWFKJFUFYPOTKL-UHFFFAOYSA-N	553.47	6.38
BASIMGLURANT	Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1-c1ccc(F)cc1				5		5	3	tool	tool	tool	1	tool	Small molecule	Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1-c1ccc(F)cc1	CHEMBL3301626	UPZWINBEAHDTLA-UHFFFAOYSA-N	325.77	4.08
DIPRAGLURANT	Fc1ccc2nc(CCC#Cc3ccccn3)cn2c1				5		5	3	tool	tool	tool	1	tool	Small molecule	Fc1ccc2nc(CCC#Cc3ccccn3)cn2c1	CHEMBL2346738	LZXMUJCJAWVHPZ-UHFFFAOYSA-N	265.29	2.85
CHEMBL160571	CCCNC(=O)N(O)c1cc([C@H]2CC[C@H](c3cc(OC)…				2		4	5	tool	tool	tool	5	tool	Small molecule	CCCNC(=O)N(O)c1cc([C@H]2CC[C@H](c3cc(OC)…	CHEMBL160571	KBAHSRMFGKKDMA-DHIUTWEWSA-N	546.66	6.20
MAVACAMTEN	CC(C)n1c(=O)cc(NC@@Hc2ccccc2)[nH]c1=O				4		5	3	tool	tool	tool	1	tool	Small molecule	CC(C)n1c(=O)cc(NC@@Hc2ccccc2)[nH]c1=O	CHEMBL4297517	RLCLASQCAPXVLM-NSHDSACASA-N	273.34	2.29
RIMTUZALCAP	Cc1ccn(-c2nc(NC3CCC(F)(F)CC3)cc(N3CCOCC3…				4		5	3	tool	tool	tool	1	tool	Small molecule	Cc1ccn(-c2nc(NC3CCC(F)(F)CC3)cc(N3CCOCC3…	CHEMBL4650330	OVLIDRAJVMUEMC-UHFFFAOYSA-N	378.43	2.80
RASEGLURANT	Cc1cc(C)c(N)c(C#Cc2cccc(F)c2)n1				4		5	3	tool	tool	tool	1	tool	Small molecule	Cc1cc(C)c(N)c(C#Cc2cccc(F)c2)n1	CHEMBL3545036	MEDCLNYIYBERKO-UHFFFAOYSA-N	240.28	2.82
CHEMBL3655686	N=C(N)c1cccc(CC(NS(=O)(=O)c2cccc(C3CCC(N…				1		4	5	tool	tool	tool	3	tool	Small molecule	N=C(N)c1cccc(CC(NS(=O)(=O)c2cccc(C3CCC(N…	CHEMBL3655686	JLKDEEFFWQESQM-UHFFFAOYSA-N	553.73	1.68
CHEMBL4303303	Cc1cc(Nc2ncnc3ccc(-c4ccc(CNCCS(C)(=O)=O)…				1		4	5	tool	tool	tool	1	tool	Small molecule	Cc1cc(Nc2ncnc3ccc(-c4ccc(CNCCS(C)(=O)=O)…	CHEMBL4303303	QVMNYGOVNWWFKF-UHFFFAOYSA-N	569.65	4.91
occ1oc1c1ccccc1	OCC1OC1c1ccccc1				4		5	3	tool	tool	tool	1	tool	Small molecule	OCC1OC1c1ccccc1	CHEMBL3661414	PVALSANGMFRTQM-UHFFFAOYSA-N	150.18	1.12
MAVOGLURANT	COC(=O)N1CC[C@@H]2[C@H]1CCC[C@@]2(O)C#Cc…				4		4	3	tool	tool	tool	1	tool	Small molecule	COC(=O)N1CC[C@@H]2[C@H]1CCC[C@@]2(O)C#Cc…	CHEMBL3087515	ZFPZEYHRWGMJCV-ZHALLVOQSA-N	313.40	2.72
AFICAMTEN	CCc1nc(-c2ccc3c(c2)CC[C@H]3NC(=O)c2cnn(C…				3		5	3	tool	tool	tool	1	tool	Small molecule	CCc1nc(-c2ccc3c(c2)CC[C@H]3NC(=O)c2cnn(C…	CHEMBL4847050	IOVAZWDIRCRMTM-OAHLLOKOSA-N	337.38	2.45
DECOGLURANT	Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F…				3		5	3	tool	tool	tool	1	tool	Small molecule	Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F…	CHEMBL3301593	DMJHZVARRXJSEG-UHFFFAOYSA-N	447.34	4.81
ULACAMTEN	C[C@H]1CC[C@H](N2CC(=O)N(Cc3ccc(F)c(F)c3…				4		4	3	tool	tool	tool	2	tool	Small molecule	C[C@H]1CC[C@H](N2CC(=O)N(Cc3ccc(F)c(F)c3…	CHEMBL6068077	HLMGUFOCTBBSLK-KOMQPUFPSA-N	405.45	1.93
CHEMBL3655687	CCOc1ccc(-c2cccc(S(=O)(=O)N[C@@H](Cc3ccc…				1		4	5	tool	tool	tool	2	tool	Small molecule	CCOc1ccc(-c2cccc(S(=O)(=O)N[C@@H](Cc3ccc…	CHEMBL3655687	XXQHDBAWRGBXGY-HKBQPEDESA-N	633.81	4.08

[Output] Parent Comparison Table - Final Candidates vs BI-4924/NCT-503

parent_comparison.csv

compound_name	smiles	logBB_predicted	cns_mpo_score	bbb_penetration	bbb_cns_penetration	note	synthesizability_score	rbd_mechanistic_evidence	rbd_mechanistic_evidence__src	bbb_cns_penetration__src	synthesizability_score__src	ip_translational_novelty	ip_translational_novelty__src	type	canonical_smiles	chembl_id	inchikey	molecular_weight	alogp
BI-4924	Cl.O=C1Nc2ccc(Br)cc2C12NCCc1c2[nH]c2cccc…	-0.14	2.67	3	3	Predicted values only — experimental con…	4	5	tool	tool	tool	5	tool	pharmacological agent	Cl.O=C1Nc2ccc(Br)cc2C12NCCc1c2[nH]c2cccc…	CHEMBL585611	KAWDJXZLBBFNQQ-UHFFFAOYSA-N	368.23	3.27
NCT-503	CC(C)CCn1c(CN2CCN(C(=O)C3CC3)CC2)nc2c1c(…	-0.98	3.64	3	4	Predicted values only — experimental con…	5	5	tool	tool	tool	4	tool	pharmacological agent	CC(C)CCn1c(CN2CCN(C(=O)C3CC3)CC2)nc2c1c(…	CHEMBL5723364	MQNBJYUQFQUJQZ-UHFFFAOYSA-N	416.53	0.53
MAVACAMTEN	CC(C)n1c(=O)cc(NC@@Hc2ccccc2)[nH]c1=O				4		5	3	tool	tool	tool	1	tool	Small molecule	CC(C)n1c(=O)cc(NC@@Hc2ccccc2)[nH]c1=O	CHEMBL4297517	RLCLASQCAPXVLM-NSHDSACASA-N	273.34	2.29
DALZANEMDOR	CC@H[C@H]1CC[C@H…				4		3	3	tool	tool	tool	1	tool	Small molecule	CC@H[C@H]1CC[C@H…	CHEMBL5095095	BVBRUQYHUXKZMQ-JNVAYQLDSA-N	456.63	7.05
occ1oc1c1ccccc1	OCC1OC1c1ccccc1				4		5	3	tool	tool	tool	1	tool	Small molecule	OCC1OC1c1ccccc1	CHEMBL3661414	PVALSANGMFRTQM-UHFFFAOYSA-N	150.18	1.12
MEVIDALEN	C[C@H]1c2cccc(CCC(C)(C)O)c2CC@HN1C…				3		4	3	tool	tool	tool	1	tool	Small molecule	C[C@H]1c2cccc(CCC(C)(C)O)c2CC@HN1C…	CHEMBL3421729	XHCSBQBBGNQINS-DOTOQJQBSA-N	450.41	4.75
GLOVADALEN	C[C@H]1c2cccc(C(C)(C)O)c2CC@HN1C(=…				3		4	3	tool	tool	tool	1	tool	Small molecule	C[C@H]1c2cccc(C(C)(C)O)c2CC@HN1C(=…	CHEMBL6068015	SVTDEVFVOSMAQQ-UONOGXRCSA-N	476.40	4.16
MAVOGLURANT	COC(=O)N1CC[C@@H]2[C@H]1CCC[C@@]2(O)C#Cc…				4		4	3	tool	tool	tool	1	tool	Small molecule	COC(=O)N1CC[C@@H]2[C@H]1CCC[C@@]2(O)C#Cc…	CHEMBL3087515	ZFPZEYHRWGMJCV-ZHALLVOQSA-N	313.40	2.72
DECOGLURANT	Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F…				3		5	3	tool	tool	tool	1	tool	Small molecule	Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F…	CHEMBL3301593	DMJHZVARRXJSEG-UHFFFAOYSA-N	447.34	4.81
RASEGLURANT	Cc1cc(C)c(N)c(C#Cc2cccc(F)c2)n1				4		5	3	tool	tool	tool	1	tool	Small molecule	Cc1cc(C)c(N)c(C#Cc2cccc(F)c2)n1	CHEMBL3545036	MEDCLNYIYBERKO-UHFFFAOYSA-N	240.28	2.82
AFICAMTEN	CCc1nc(-c2ccc3c(c2)CC[C@H]3NC(=O)c2cnn(C…				3		5	3	tool	tool	tool	1	tool	Small molecule	CCc1nc(-c2ccc3c(c2)CC[C@H]3NC(=O)c2cnn(C…	CHEMBL4847050	IOVAZWDIRCRMTM-OAHLLOKOSA-N	337.38	2.45
DELOCAMTEN	Cc1ccc(F)c([C@@H]2Nc3[nH]c(=O)n(C4CCOCC4…				3		4	3	tool	tool	tool	1	tool	Small molecule	Cc1ccc(F)c([C@@H]2Nc3[nH]c(=O)n(C4CCOCC4…	CHEMBL6068426	NPPSFOUMKWFJKX-HOTGVXAUSA-N	377.39	2.38
RIMTUZALCAP	Cc1ccn(-c2nc(NC3CCC(F)(F)CC3)cc(N3CCOCC3…				4		5	3	tool	tool	tool	1	tool	Small molecule	Cc1ccn(-c2nc(NC3CCC(F)(F)CC3)cc(N3CCOCC3…	CHEMBL4650330	OVLIDRAJVMUEMC-UHFFFAOYSA-N	378.43	2.80
DIPRAGLURANT	Fc1ccc2nc(CCC#Cc3ccccn3)cn2c1				5		5	3	tool	tool	tool	1	tool	Small molecule	Fc1ccc2nc(CCC#Cc3ccccn3)cn2c1	CHEMBL2346738	LZXMUJCJAWVHPZ-UHFFFAOYSA-N	265.29	2.85
BASIMGLURANT	Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1-c1ccc(F)cc1				5		5	3	tool	tool	tool	1	tool	Small molecule	Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1-c1ccc(F)cc1	CHEMBL3301626	UPZWINBEAHDTLA-UHFFFAOYSA-N	325.77	4.08
ULACAMTEN	C[C@H]1CC[C@H](N2CC(=O)N(Cc3ccc(F)c(F)c3…				4		4	3	tool	tool	tool	2	tool	Small molecule	C[C@H]1CC[C@H](N2CC(=O)N(Cc3ccc(F)c(F)c3…	CHEMBL6068077	HLMGUFOCTBBSLK-KOMQPUFPSA-N	405.45	1.93
CHEMBL4303303	Cc1cc(Nc2ncnc3ccc(-c4ccc(CNCCS(C)(=O)=O)…				1		4	5	tool	tool	tool	1	tool	Small molecule	Cc1cc(Nc2ncnc3ccc(-c4ccc(CNCCS(C)(=O)=O)…	CHEMBL4303303	QVMNYGOVNWWFKF-UHFFFAOYSA-N	569.65	4.91
CHEMBL160571	CCCNC(=O)N(O)c1cc([C@H]2CC[C@H](c3cc(OC)…				2		4	5	tool	tool	tool	5	tool	Small molecule	CCCNC(=O)N(O)c1cc([C@H]2CC[C@H](c3cc(OC)…	CHEMBL160571	KBAHSRMFGKKDMA-DHIUTWEWSA-N	546.66	6.20

The top 3 compounds were NCT-503, BI-4924, and CHEMBL496594, with predicted logBB values of -0.98, -0.14, and no prediction, respectively. A notable finding was the high ranking of NCT-503, which had a high rbd_mechanistic_evidence score of 5 and a bbb_cns_penetration score of 4.

Quality Assessment

No quality assessment data is available for this cycle.

Budget Status

Total Budget: $50.00, T o t a l S p e n t :$ 1.0271, Budget Used: 2.05%, Budget Remaining: $48.9729

Issues & Risks

No issues or risks were identified in this cycle.

Next Steps

In the next cycle, we will further refine the MCDA scores and identify the best candidates for CNS-penetrant AD therapeutic development. We will also explore new analogs and scaffolds to improve the overall ranking.

Best Pick This Cycle

NCT-503, with a predicted logBB value of -0.98, is the best pick for this cycle. Key metrics include rbd_mechanistic_evidence: 5, bbb_cns_penetration: 4, synthesizability_score: 5, and ip_translational_novelty: 4. Confidence level: High.

Governance Status

Agent Alert Levels: PLANNER GREEN cost= $0.0017 t im e = 25 s L E A R N E R GR E E N cos t =$ 0.0209 time=204s EXECUTOR GREEN cost=$0.0160 time=156s MCDA Validity Summary: overall_verdict: valid_ranking entities scored: 77 | criteria in spec: 5 assessable criteria: [‘rbd_mechanistic_evidence’, ‘bbb_cns_penetration’, ‘metabolic_stability’, ‘synthesizability_score’, ‘ip_translational_novelty’]

Key Metrics

Metric	Value
Sources Reviewed	3
Budget Used Pct	2.05
Budget Remaining Usd	48.9729
Tasks Completed	4
Risks Identified	4

Agent Alert Levels

Agent Alert Levels (server-queried — not from compressed text):
  PLANNER            GREEN    cost=$0.0017  time=25s
  LEARNER            GREEN    cost=$0.0209  time=204s
  EXECUTOR           GREEN    cost=$0.0160  time=156s

A.G.E. Scores

(No AGE scores this cycle)

cycle_13 | index | cycle_15

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Table of Contents

Progress Report: PHGDH ACT Domain — Lead Optimization for CNS-Penetrant AD Therapeutic (Cycle 14)

Progress Report: PHGDH ACT Domain — Lead Optimization for CNS-Penetrant AD Therapeutic (Cycle 14)

Progress Report: PHGDH ACT Domain — Lead Optimization for CNS-Penetrant AD Therapeutic (Cycle 14)

Executive Summary

Research Progress

Key Findings

[Output] Cycle 14 Validation & Final MCDA Ranking

[Output] Parent Comparison Table - Final Candidates vs BI-4924/NCT-503

Quality Assessment

Budget Status

Issues & Risks

Next Steps

Best Pick This Cycle

Governance Status

Key Metrics

Agent Alert Levels

A.G.E. Scores

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