Table 3. Structure–Activity Relationships for 4-Phenyl Modifications on Trisubstituted Hydroxylactams^a.

compd	R	LDHA IC50 (μM)	LDHB IC50 (μM)	MiaPaca2 Lactate IC50 (μM)	LogD7.4
21	cyclohexyl	0.025	0.18	25	3.5
24	1-(4-OMe)piperidinyl	0.016	0.075	2.9	1.2
29-R	1-morpholino	0.003	0.005	0.67	0.6
31	2,6-dimethylmorpholino	0.027	0.14	3.9	1.3
32	3-oxomorpholino	0.021	0.080	>50	0.4
33	2,2-dimethylmorpholino	0.015	0.070	5.1	1.3
34	1,1-dioxidothiomorpholino	0.013	0.046	>50	ND
35	1-(4-spiro-oxetanyl)piperidinyl	0.017	0.14	9.9	0.7
36	1(4-cyano)piperidinyl	0.010	0.060	6.1	0.8

^aMiaPaca2 cell assay values are the geometric mean of at least 2 separate runs as previously described.²¹ LogD_7.4 was measured via a high throughput method.²²